Advertisement
Minireview

Modulation of Cellular Signaling Pathways

Prospects for Targeted Therapy in Hematological Malignancies

Farhad Ravandi, Moshe Talpaz and Zeev Estrov
DOI:  Published February 2003

Abstract

The high remission rates observed in patients with chronic myelogenous leukemia who receive Imatinib mesylate (Gleevec) indicate that targeted therapy for hematological malignancies is achievable. At the same time, progress in cellular biology over the past decade has resulted in a better understanding of the process of malignant transformation, a better classification of subtypes of each disease on the basis of molecular markers, and a better characterization of the molecular targets for drug development. These advances have already spawned the development of such effective agents as monoclonal antibodies and specific enzyme inhibitors. This review attempts to provide a practical introduction to the complex and growing field of targeted therapy in hematological malignancies.

Introduction

Cellular proliferation, differentiation, and death are regulated by a number of extracellular molecules such as cytokines and hormones, as well as intercellular interactions mediated by neighboring cell surface antigens. These effectors mediate gene transcription either directly or indirectly by activating intracellular signaling pathways, which in turn activate appropriate cellular machinery (1) . Cell-surface receptors that convert external stimuli into intracellular signals are pivotal in this signaling process. They activate intracellular pathways either through their inherent enzymatic function or as a result of their association with other catalytic proteins. Indeed, most growth factors and cytokines bind these receptors and exert their function through their activation, commonly by phosphorylation (1) .

Normal hematopoiesis is dependent on intricately regulated signaling cascades that are mediated by cytokines and their receptors. Orderly function of these pathways leads to the generation of appropriate constellation of hematopoietic cells, and their abnormal activation results in neoplastic transformation, impaired apoptosis, and uncontrolled proliferation. Cytokines function in a redundant and pleiotropic manner; different cytokines can exert similar effects on the same cell type, and any particular cytokine can have several differing biological functions (2) . This complexity of function is a result of shared receptor subunits as well as overlapping downstream pathways culminating in activation of common transcription factors (3) .

The signal transduction cascades involve three major classes of proteins: kinases, adaptor or docking proteins, and transcription factors. Early insights into the cellular signaling pathways came from studies of IFN function (4, 5, 6) . These experiments led to the identification of a family of nonreceptor TKs2 called Jaks and their target proteins, Stats, which mediate gene transcription (4 , 7) . The Jak-Stat pathways are commonly activated during cytokine signaling through phosphorylation of specific tyrosine residues (3) . The interaction of a cytokine with its receptor induces its tyrosine phosphorylation and leads to activation of downstream protein TKs including Jaks and Stats. Apart from their catalytic domain, protein TKs contain several other characteristic motifs including the SH2, SH3, and pleckstrin homology domain, which enable them to interact with other signaling molecules and propagate the message (8 , 9) .

The phosphorylation of serine and threonine residues is integral to the activation of numerous other intracellular proteins that mediate a number of other signaling pathways (10) . Cytokine receptors without intrinsic kinase activity transmit their signals primarily through activation of Jak kinases. These receptors as well as those with intrinsic kinase activity, the RTKs, were previously thought to transmit their signals independently of the serine/threonine kinase cascades. More recently, it has been established that both of these pathways interact with serine/threonine kinase cascades such as the Ras/Raf/MEK/ERK (MAPK; Ref. 10 ). For example, after ligand binding, the βsubunit of IL-3 and GM-CSF receptors are phosphorylated and, through recruitment of adaptor proteins such as Shc, Grb2, and Sos, activate the Ras signaling pathway (11) . This in turn activates Raf followed by downstream activation of ERK1 and ERK2, and increased expression of transcription factors c-fos and c-jun (12, 13, 14) . Other members of the MAPK family such as p38, and JNK/SAPK are also activated after phosphorylation of their serine/threonine residues as a result of cytokine/receptor interaction (15, 16, 17, 18) . Similarly, PI3K associates with the β chain of IL-3 receptor, recruits PKB/AKT by phosphorylation of its serine residues, and transmits cellular survival signals (19, 20, 21) . Another downstream protein to IL-3 activation is the p70S6 kinase, which also interacts with the β chain and mediates appropriates signals (22 , 23) . Ultimately, these pathways influence gene transcription through their ability to recruit transcription factors, regulate apoptosis through the phosphorylation of apoptotic proteins, and cause the cell to progress through cell-cycle checkpoints by activation of specific kinases.

Of considerable interest is the description of a number of oncogenes with constitutive kinase activity. These molecules are derived from genes including c-ABL, c-FMS, FLT3, c-KIT, and PDGFRβ, which are normally involved in the regulation of hematopoiesis (24) . The kinase activity of the oncogene is constitutively activated by mutations that remove inhibitory domains of the molecule or induce the kinase domain to adopt an activated configuration (24) . As a result of such constitutive activation a number of signaling cascades such as the Jak-Stat pathway, the Ras/Raf/MAPK pathway, and the PI3K pathway are activated.

With better characterization of aberrant signaling through the cell surface receptors and their downstream pathways in neoplastic cells, current research is exploring ways to reverse such dysregulated stimuli (25) . Here, we will briefly review the role of cellular signaling pathways in normal cellular processes, neoplastic transformation, and development of hematological malignancies. We then explore the possible ways that their modulation can lead to clinically meaningful benefits.

Jak-Stat Signaling Pathways

Hematopoietic cell proliferation and differentiation is regulated by a number of soluble polypeptides such as IFNs, interleukins, and colony-stimulatory factors known collectively as cytokines (26) . Cytokines bind to their cognate receptors and mediate downstream effects. A cytokine receptor consists of a unique ligand binding subunit as well as a signal transducing subunit, which may be structurally similar to the other cytokine receptors (27, 28, 29) . On the basis of their characteristic structural motifs in their extracellular domains a number of subfamilies of cytokine receptors have been identified (27 , 29 , 30) . These include the gp130 family, the IL-2 receptor family, the growth hormone receptor family, the IFN family, and the gp140 family of receptors (3) . A detailed description of the structure of these receptors is beyond the scope of this review, but in general they consist of two or more subunits including the α, β, and γ chains (3 , 27) . For example, the IL-2 receptor family includes the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 each consisting of a ligand-binding α-subunit, and signal transducing β and γ subunits. Alternatively, the gp140 family including the receptors for IL-3, IL-5, and GM-CSF have a unique ligand-binding α-subunit and a common β (gp140) signal-transducing unit (3) .

Unlike growth factor receptors (RTKs), cytokine receptors do not possess a cytoplasmic kinase domain, and most cytokines transmit their signal by recruiting other TKs (3) . Dimerization of the cytoplasmic component of the cytokine receptor as a result of ligand binding is the initial step in the initiation of cellular signaling (31) . The dimerized subunits then associate with intracellular TKs such as members of the Src or Jak families of kinases, and the signal is propagated (Fig. 1)⇓ . Different Src family members are associated with different receptors and phosphorylate distinct but overlapping sets of downstream target molecules. For example, Lck, Lyn, and Fyn can be activated by IL-2 (29 , 32) .

Fig. 1.
Fig. 1.

The Jak-Stat pathway and its regulation.

The Jak family of kinases comprises four known relatively large proteins (Jak1, Jak2, Jak3, and Tyk2) that can bind cytokine receptor subunits, phosphorylate them, and in doing so creat docking sites on the receptors for binding of SH2-containing proteins (33 , 34) . In general, Jaks consist of several domains (JH1-JH7) of which the functional significance has been characterized by mutational analysis and include a TK domain (JH1; Refs. 3 , 33 , 35 , 36 ). The precise functions of JH2-JH7 domains are under current investigation (3) . Jaks are able to associate with the cytokine receptors as well as with each other (37 , 38) . Dimerization/oligomerization of cytokine receptor subunits as a result of ligand binding leads to juxtaposition of Jaks (3) . This results in transphosphorylation and activation of their kinase activity and the phosphorylation of downstream signaling proteins such as Stats, Src-kinases, and adaptors such as Shc, Grb2, and Cbl (Fig. 1⇓ ; Refs. 39 , 40 ).

Abnormalities of Jak function have been associated with a number of disorders (34 , 41) . For example, chromosomal translocations resulting in TEL-JAK2 constructs lead to the constitutive activation of Stat5, IL-3-independent cellular proliferation, and leukemogenesis (42 , 43) . The translocation t(9;12)(p24;p13) results in the fusion of the kinase catalytic region of JAK2 with the transcription factor TEL generating the constitutively active TEL-JAK2. Similarly, infection with oncogenic viruses such as human T-cell lymphotrophic virus, type I, and Abelson murine leukemia viruses results in enhanced TK activity of Jaks, possibly accounting for their leukemogenic potential (44 , 45) .

The Stat transcription factors are coded by six known mammalian genes and include 10 different Stat proteins including different isomers of Stats 1, 3, 4, and 5 (3 , 46) . Like other transcription factors Stats have a well-defined structure including a DNA-binding domain, a conserved NH2-terminal domain, a COOH-terminal transactivation domain, and SH2 and SH3 domains (3) . Their activation through tyrosine phosphorylation results in their dimerization and translocation into the nucleus where they activate specific genes (6 , 47, 48, 49) .

Jak proteins activate a number of intracellular signaling proteins, among which Stats are the best defined (46 , 50) . Binding of a cytokine to its receptor rapidly induces tyrosine phosphorylation of the cytoplasmic domains of the receptor by activated Jak kinases, thus providing a docking site for Stat proteins, which are then phosphorylated. This phosphorylation of Stats leads to their homo- or heterodimerization and translocation to the nucleus, followed by DNA binding and gene activation (Fig. 1⇓ ; Refs. 51 , 52 ). The specificity for Stat phosphorylation is determined by the receptor docking sites and not the Jak kinases (53 , 54) . Also, different Stat proteins have different DNA-binding affinities, resulting in activation of specific genes. Stats also interact with other transcription factors such as the p300/cyclic AMP-responsive element binding protein family of coactivators to activate genes (55 , 56) . The transcriptional activity of Stats may also be regulated by the phosphorylation of their serine and threonine residues, although the implications of such regulation are not known (7 , 57) .

Stats mediate diverse and sometimes opposite cellular events affecting growth, differentiation, and apoptosis (58 , 59) . For example, Stats can mediate both growth arrest and cellular proliferation. Specifically, Stat1 mediates the growth-inhibitory effects of IFN-γ, through the induction of the CDKI p21waf1, whereas Stat5 mediates proliferative effects of IL-3 and GM-CSF (60 , 61) . Similarly, phosphorylation of Stat3 can result both in IL-6- and IL-10-induced growth arrest, and in GM-CSF- and IL-3-induced proliferation (61, 62, 63) . Stats also modulate cellular differentiation and apoptosis. Reconstitution of Stat1 in Stat1-null U3A cells (which do not respond to TNF-α) restores basal caspase expression and renders them sensitive to TNF-induced apoptosis (64) . Conversely, Stat3 and Stat5 mediate the antiapoptotic effects of IL-6 and IL-2, respectively (65 , 66) . Stat1 activates the caspase cascade through up-regulation of Fas and FasL expression in response to IFN-γ (67) . The exact mechanisms underlying these diverse effects are being elucidated.

An important property of cellular signaling pathways is that their activation is both rapid and transient. This is because of effective mechanisms of inactivation. In the Jak-Stat system, proteasome-mediated degradation, tyrosine dephosphorylation, and inhibition by various inhibitory proteins are responsible for this process (4) . The ubiquitin-proteasome pathway governs the degradation of many intracellular proteins including activated Stats, and effective inhibitors of this system have shown promising early results in clinical trials (68 , 69) . The cytokine-activated Jak-Stat pathways are also inhibited by tyrosine dephosphorylation mediated by cytoplasmic phosphatases such as SHP-1 (70 , 71) . SHP-1-deficient mice demonstrate multiple hematopoietic abnormalities, including hyperproliferation and abnormal activation of granulocytes and macrophages in the lungs and in the skin (72) . SOCS and PIAS are other important inhibitors of the activated Jaks and Stats (70 , 73) . Recent studies have established that SOCS are negative regulators of cytokines, and there is ample evidence suggesting the importance of Stats in the induction of SOCS expression, thereby constituting a negative feedback mechanism (74, 75, 76) . The role of these inhibitory proteins in the pathogenesis of neoplastic transformation is also becoming clearer (77) .

RTK and Serine/Threonine Signaling Pathways

RTKs are membrane-bound enzymes with an extracellular ligand-binding domain, a transmembrane domain, and a highly conserved intracellular domain that mediates the activation, through tyrosine phosphorylation, of a number of downstream signaling proteins (78, 79, 80) . These enzymes are activated by ligand binding, by cell-cell interactions via cell adhesion molecules, and by stimulation of G-protein coupled receptors (81) . Phosphorylated tyrosine residues in specific domains of these receptors serve as high-affinity docking sites for SH2-containing adaptor and effector proteins (82) . RTKs include diverse molecules, which are considered as members of several distinct classes: class I including epidermal growth factor receptor; class II including insulin-like growth factor-1 receptor; class III including PDGFR, macrophage colony-stimulating factor (FMS-R or CSF-1R), stem cell factor receptor (KIT), and FLT3R; and class IV including FGFR (79 , 83 , 84) . The importance of these receptors in malignant transformation and the possibility of modulating them as therapeutic targets are subjects of intense research. The recent reports of constitutive activation of FLT3R resulting in stimulation of multiple signaling pathways and leading to malignant transformation has been of significant interest in leukemia research (85 , 86) . Such constitutive activation of this receptor has been reported in >30% of patients with AML and results from two well-described molecular events. Internal tandem duplication mutations of FLT3R gene occur at exons 11 and 12 of the gene that code for the juxtamembrane domain of receptor (87, 88, 89, 90) . More recently, point mutations of codon 835 of FLT3R receptor gene, located in the activation loop of its TK domain, have been reported in 7% of patients with AML (87 , 91) . Inhibitors of such aberrant activation are undergoing clinical evaluation (92 , 93) .

Many intracellular signaling proteins bind the phosphotyrosine on the activated RTKs. These proteins include GTPase activating protein, PI3K, Grb2, and Src-like tyrosine-kinases (1 , 10 , 78) . The activation of these proteins by serine/threonine phosphorylation in turn activates a number of downstream signaling cascades that lead to gene transcription (10) .

Although knowledge of the Jak-Stat pathway has been instrumental in understanding cytokine signaling (94) , the importance of signaling cascades that involve the activation of serine/threonine kinases is increasingly apparent (10) . The serine/threonine MAPKs, which include the Ras-Raf-MEK-ERK pathway, the p38 family of kinases, and the JNK (SAPK) family, are activated by upstream signals and mediate effects on inflammation, cell growth, cell cycle progression, cell differentiation, and apoptosis (95) . The Ras family of proteins belongs to the large superfamily of GTPases that localize to the inner surface of the plasma membrane (1 , 96) . Ras proteins play a pivotal role in a number of signaling pathways mediated by RTKs and other receptors. Ligand binding to these receptors initiates the autophosphorylation of specific tyrosine residues in their cytoplasmic domain and creates phosphotyrosyl-binding sites for adapter proteins such as Shc and Grb2, which in turn recruit guanine nucleotide exchange factors and thereby initiate Ras activation (97 , 98) .

Once induced, Ras activates Raf serine/threonine kinase, which then phosphorylates MAPK kinases (otherwise known as MEKs; Refs. 10 , 97 , 99 ). These in turn activate MAPKs (or ERKs; Refs. 100 , 101 ), which in turn move to the nucleus where they phosphorylate and activate nuclear transcription factors such as Elk-1 (102) . ERKs were initially described as a novel family of protein kinases that, when activated, produced proliferative stimuli (103) . ERKs can also activate other kinases such as RSKs (also known as MAPK-activated protein kinases), which are involved in cell-cycle regulation and apoptosis (104) . ERK-activated RSK kinase catalyzes the proapoptotic protein Bad and suppresses Bad-mediated apoptosis (105) . Similarly, the Ras-Raf-MEK-ERK cascade modulates cellular proliferation by regulating the activity of several proteins, including cell-cycle regulators (e.g., cyclin D1, p21waf1/cip1, p27kip1, and cdc25A) and transcription factors (e.g., c-Myc; Ref. 106 ).

The G1/S cell cycle checkpoint is a critical point determining the commitment of cells to growth arrest or proliferation. During this stage cells are responsive to cytokines (107) . Regulatory proteins p21waf1/cip1 and p27kip1 are of particular importance in this transition, which is controlled by both positive and negative regulators. Distinct Rb-E2F repressor complexes suppress the transcription of genes required for progression of various phases of cell cycle. For example, Rb-E2F1 complex suppresses the progression through G1 (108) . During this progression from G1 to S-phase cyclin/CDKs are sequentially activated, which then inactivate suppressor complexes such as Rb-E2F1 (109) . Cyclin/CDK activity results in Rb phosphorylation and its dissociation from E2F1 leading to activation of genes necessary for S phase (110) . Activity of a number of these cyclin/CDKs as well their inhibitors such as p21waf1/cip1 is modulated by cytokine-mediated signals through their phosphorylation.

The p38 family of MAPKs is involved in various cellular processes such as inflammation, cell cycle progression, and cell death (111 , 112) . The four different p38 isoforms (α, β, γ, and δ) are activated by two MEK isoforms (113) . Originally, the p38 kinase pathway was reported to have a critical role in the generation of signals in response to stress stimuli. However, its role in cytokine signaling and regulation of the Jak-Stat pathway has been elucidated recently (114) . In particular, from the standpoint of leukemogenesis, it modulates the growth-inhibitory effect of type I IFNs in BCR-ABL-expressing cells as well as normal hematopoietic progenitors (115 , 116) .

The third group of MAPKs includes the JNK (otherwise known as SAPK; Ref. 95 ). The four different JNK kinases have a similar role to p38 kinases in cellular function and are activated by specific MAPK kinases (MEKKs) in response to inflammatory cytokines such as TNF-α, and other stress stimuli such as reactive oxygen species, heat, and withdrawal of growth factors (117) . The MEKK1/JNK signaling increases p53 stability and transcriptional activation, and MEKK1/JNK potentiates the ability of p53 to initiate apoptosis (118) .

Normal functioning of MAPK-mediated signaling necessitates its efficient inactivation (95) . A number of dual-specificity MAPK phosphatases serve to dephosphorylate and, hence, inactivate MAPKs (119, 120, 121) . Similarly, protein phosphatases PP1 and PP2 dephosphorylate and inactivate a number of phosphoproteins including components of the MAPK pathway (122 , 123) .

Other signaling pathways such as those mediated by PI3K, AKT (also known as PKB), and protein kinase C are also controlled by serine/threonine phosphorylation (Fig. 2⇓ ; Ref. 10 ). PI3K consists of two subunits, the p85 regulatory subunit and the p110 catalytic subunit (124 , 125) . The p85 subunit binds to the cytokine receptor as a consequence of ligand-receptor interaction and receptor autophosphorylation (126) . As a result, phosphatidylinositol-dependent kinases and their downstream substrate AKT/PKB are recruited to the membrane (127) . PI3K-AKT pathway activates several downstream targets including p70 RSK, forkhead transcription factors, and NFκB (128, 129, 130) . The serine/threonine kinase AKT is an important component of the cell survival machinery (10 , 131, 132, 133) . Its activation via the PI3K pathway leads to a number of events (10 , 131 , 134 , 135) . For example, the phosphorylation of the cytosolic protein IκB by AKT releases NFκB from its association with IκB. NFκB then moves into the nucleus, where it induces a number of genes involved in cell survival (131) . Meanwhile, the inhibitory protein IκB is degraded by the proteasome (136) . AKT also phosphorylates the proapoptotic protein Bad, which leads to higher levels of free antiapoptotic Bcl-xL and thereby inhibits the cell-death protease caspase-9 (134) . The tumor suppressor gene PTEN codes for a phosphatase that acts by removing a phosphate group from the 3 position of the inositol ring of the PIP3,4,5 phospholipids located at the cellular membrane. This prevents the proximation of AKT and phosphatidylinositol-dependent kinases, and prevents AKT activation (137, 138, 139, 140) . Several lines of evidence including studies of PTEN knockout mice support the role of PTEN as a tumor suppressor gene (141) . Serine/threonine kinases, in general, also influence the activity of other antiapoptotic proteins of the Bcl-2 family (10 , 135 , 142) . In the normal cell cycle, Bcl-2 is phosphorylated on its serine/threonine residues at several points during the G2 to M phase transition (10 , 143) .

Fig. 2.
Fig. 2.

Interactions of diverse signaling pathways.

PKC, another important signaling enzyme, phosphorylates specific serine or threonine residues on target proteins in different ways (Fig. 2)⇓ . For example, PKC is a potent activator of Raf-1, which activates the MAPK cascade. This leads to phosphorylation of IκB, release of NFκB, translocation of NFκB into the nucleus, and gene transcription as described above (144, 145, 146) . PKC also regulates cytokine signals through its effects on the Jak-Stat pathway in some myeloid progenitor cell lines (147) . The significant role of PKC in phosphorylation and activation of Raf has led to its targeting for inhibition of the Raf-Ras-MEK-ERK pathway (95 , 148) . For example, staurosporine analogs UCN-O1 and CGP 41251 are being examined as inhibitors of PKC and MAPK signaling (149 , 150) .

Various signaling pathways interact resulting in their modulation at several levels. For example, PI3K interacts with and enhances Raf-Ras-MEK-ERK pathway (151, 152, 153) . Other serine/threonine phosphorylation pathways modulate cytokine signals through the Jak-Stat pathway (10 , 154) . In addition to being tyrosine phosphorylated, several Stats (Stat1α, Stat3, and Stat4) are serine phosphorylated by ERKs at conserved serine residues (155) . In fact, during cytokine signaling, Jak and Raf kinases carry on an intricate cross-talk (10) .

Therapeutic Implications

Signaling pathways may be particularly attractive targets in cancer therapy because they may be inappropriately activated in malignant cells. However, several factors must be carefully considered while developing agents that modulate these pathways. One is the possible toxicity of such therapy. Because these pathways are activated to a significantly greater degree in malignant cells than normal cells, their partial inhibition may be sufficient to interfere with malignant cell growth without causing significant toxicity (25) . Therefore, despite the pivotal role of these pathways in normal cellular function, their inhibition may not be toxic to normal cells.

Another point of consideration in designing inhibitors is the specificity of the target pathway and the selectivity of its inhibitors. Adding to this challenge is the fact that these pathways are part of a complex network of interconnecting cascades resulting in a certain degree of redundancy and overlap.

Diseases induced by specific oncogenic alterations leading to constitutive activation of pivotal molecules in the pathways may provide us with such specificity and selectivity. A number of translocations occurring in hematological malignancies are known to result in fusion genes with enhanced kinase activity (24) . The oncoprotein Bcr-Abl results from a translocation between chromosomes 9 and 22, and occurs in CML and ALL. Its transforming activity is the product of activation of a number of signaling molecules such as Ras, Raf, PI3K, JNK/SAPK, Crkl, and Stat5 (156, 157, 158, 159, 160) . As a result of their activation, a number of pathways, which inhibit apoptosis and promote cell survival, are induced (24) . Bcr-Abl is constitutively phosphorylated on a number of tyrosine residues, allowing the docking of adaptor proteins such as Cbl, Crkl, Shc, and Grb2, which recruit the Ras signaling pathway, the p85 regulatory subunit of PI3K, the focal adhesion proteins paxillin and talin, and a number of other signaling pathways (159 , 161, 162, 163) . The specific Bcr-Abl inhibitor Imatinib mesylate has proven to be very effective in suppressing these pathways in vitro and in patients with CML and ALL (164, 165, 166, 167, 168, 169, 170) .

Although the platelet-derived growth factors, PDGFRα and PDGFRβ have significant homology, only the PDGFRβ has been implicated in hematological cancers where a significant number of patients with chronic myelomonocytic leukemia have t(5;12)(q33;p13) generating the fusion protein TEL-PDGFRβ (171 , 172) . As a result of ligand-independent dimerization and autophosphorylation of the PDGF β-subunit, the TK is constitutively active. PDGF is able to stimulate the growth of primitive hematopoietic, erythroid, and megakaryocytic precursors, and TEL-PDGFRβ can confer cytokine-independent growth to Ba/F3cells (173) . Imatinib mesylate inhibits the kinase PDGFRβ and has been shown anecdotally to be effective in patients with this translocation (174) .

Similarly, the chimeric gene NPM-ALK is produced as a result of translocation t(2;5)(p23;q35; Refs. 175 , 176 ). Fusion of NH2-terminal domain of NPM to the cytoplasmic region of the ALK TK receptor results in constitutive activation of its catalytic domain (177 , 178) . NPM-ALK associates with a number of adaptor proteins such as Grb2 and Crkl, and results in the activation of the downstream signaling proteins such as PI3K, AKT, and Stat5 (179, 180, 181, 182) . Therefore, design of specific inhibitors of the NPM-ALK may be of considerable interest in treating patients with anaplastic large cell lymphoma where up to 50% of patients express the chromosomal translocation (183) .

The TK modulated pathways such as the Jak-stat cascade can be targeted at several steps along the way (Fig. 3)⇓ . Because a number of cytokines and growth hormones play an important role in the suppression of apoptosis in the malignant clone in hematological cancers (e.g., IL-6 in myeloma; IL-2 in some T-cell lymphomas; and IL-1, IL-3, and GM-CSF in AML; Refs. 25 , 184 ), inhibition of the cytokines and their receptors is a plausible therapeutic strategy (185 , 186) . Furthermore, where there is constitutive activation of the receptor leading to neoplastic change, selective inhibition of kinase activity of the receptor is likely to be of benefit. For example, inhibition of FLT3-R TK activity is selectively cytotoxic to AML blasts harboring the appropriate activating mutations (92 , 187) . Activating mutations of FLT3-R including the internal tandem duplication mutation and mutation of the TK domain occur in >30% of patients with AML, confer adverse prognosis, and can be targeted by selective inhibitors (92 , 188 , 189) . Clinical trials examining the efficacy and safety of such inhibitors are currently under way. Intracellular activators of Stats such as Jaks and Src are also likely targets (164, 165, 166) . For example, the Jak2 inhibitor AG490 inhibited the growth of ALL cells in a mouse model without affecting normal hematopoiesis (190) . AG490 also acts by inhibiting Stat function, and induces apoptosis in Sezary cells and myeloma cells (191 , 192) . Furthermore, numerous other cellular TKs have been identified that likely have roles in neoplastic cell survival and proliferation, and a number of TK inhibitors are already being explored for their effects on signaling cascades. In general, two classes of TK inhibitors are being developed: inhibitors of the ATP binding site and inhibitors of the substrate binding sites (164 , 193 , 194) .

Fig. 3.
Fig. 3.

Targets for inhibition in Jak-Stat signaling pathway.

There are other ways to interrupt Stat signaling. One is the specific inhibition of the Stat SH2 domain, because it is essential for the recruitment of Stats to the receptor subunit and for Stat dimerization (25) . Antisense oligonucleotides directed at Stats (195) , modulation of the activity of natural Stat inhibitors such as SOCS and PIAS, and inhibition of the binding of activated Stat dimers to their DNA targets (25 , 196 , 197) are other mechanisms currently under investigation.

A better understanding of the effects of current antineoplastic agents on these pathways may also elucidate their mechanism of action and lead to the development of more effective and less toxic agents. For example, fludarabine causes a profound and specific loss of Stat1 (198) , which may be at least partly responsible for its antineoplastic properties as well as its immunosuppressive properties, which is similar to Stat1 knockout mice.

Multiprotein complexes, which can modify the structure of chromatin and influence gene regulation, are often aberrant in hematological malignancies. Although their interactions with various signaling pathways have not been clearly defined, they merit specific mention as they are subject of intense research. Such complexes include proteins such as HDAC, histone acetyltransferase, and DNA methyltransferases. In a significant proportion of patients with AML-M2, the translocation t(8;21)(q22;q22) results in the fusion of the DNA-binding domain of AML1 with ETO, which interacts with corepressor complexes such HDAC and repress cellular differentiation (199 , 200) . Similarly, t(12;21)(p13;q22) in childhood ALL results in recruitment of the repressor N-CoR by the fusion protein TEL-AML1 (201 , 202) . Inhibitors of HDACs and DNA methyltransferase such as butyrates, trichostatin A, 5-azacytidine, and 2′-deoxy-azacytidine are currently under investigation in clinical trials (203 , 204) .

The most common translocation in APL, t(15;17)(q22;q11.2), results in the fusion of RARα with the PML genes, with the resulting fusion protein retaining the functional domains of both (205 , 206) . The fusion protein recruits nuclear receptor corepressors SMRT and N-CoR, which together with HDACs keep the chromatin in the closed configuration and suppress/inactivate retinoid receptor target genes in myeloid development (207 , 208) . In patients with PML-RARα, pharmacological doses of ATRA can convert the fusion protein from a dominant-negative inhibitor of retinoid-regulated transcription to an activator (209) . Signaling pathways that interact with retinoid-mediated transcription may be modulated to potentiate ATRA-induced differentiation (210) . ATRA may also exert effects on upstream signaling pathways. For example, ATRA up-regulates Stat1 and Stat2 activity in the IFN-α signaling pathway, thereby potentiating the growth-inhibitory effects of IFN-α (211, 212, 213) . Another novel therapeutic agent in APL, arsenic trioxide, affects a number of cellular signaling pathways, leading to induction of apoptosis and differentiation (214, 215, 216, 217) . Therapeutic effects of arsenic trioxide in APL are partly related to its degradation of PML-RARα fusion protein through targeting PML to proteasomal degradation by Sumolation (218) . However, arsenic trioxide has a number of other effects such as activation of JNK kinases; translocation of PKC from cytosol to plasma membrane to mediate downstream signaling; enhancement of CDKIs, p21waf1/cip1, and p27kip1; and inhibition of IκB kinase and NFκB (214) .

Monoclonal antibodies such as rituximab (anti-CD20) and alemtuzumab (anti-CD52) are increasingly used in treating hematological malignancies (219, 220, 221) . Their exact mechanism of action is largely unknown. However, understanding their effects on the signaling pathways downstream of the target receptor is likely to point the way to more effective agents. The ligation of CD20 by rituximab in the presence of FcR-expressing cells may initiate signal transduction events that induce an elevation of intracellular Ca2+ and lead to apoptosis of the target malignant B cells (222) . Rituximab has also been shown in vivo to activate caspases in blood leukemia cells immediately after its infusion suggesting a mechanism of action independent of complement-mediated cell lysis or antibody-dependent cellular cytotoxicity (223 , 224) .

Inhibition of serine/threonine kinases involved in RTK signaling is another major area of research and development. As noted previously, Ras proteins play a significant role in human carcinogenesis. Therefore, inhibition of Ras signal transduction has been the subject of intense research. Ras-mediated signaling can be inhibited by prevention of its membrane localization, by inhibition of Ras protein expression using antisense nucleotides, and by inhibition of its downstream targets (95 , 225) . Pharmacological inhibitors of farnesyltransferase, the enzyme responsible for the COOH-terminal prenylation of Ras and, hence, its membrane association and transforming activity, have already been developed, and clinical trials of their efficacy in leukemia are under way (96 , 226, 227, 228, 229) . Four such farnesyl transferase inhibitors are available at various stages of testing: R115777, SCH66336, L778123, and BMS214662 (95 , 230 , 231) . FTIs may also have Ras-independent effects on other cellular signaling components that contribute to their antineoplastic action (232) . Other steps in the serine/threonine cascades, from the cell surface receptor to gene transcription, are also being examined as possible targets for therapy (Ref. 95 ; Fig. 4⇓ ). Compounds such as geldanamycin and derivatives of radicicol are known to destabilize Raf protein and interfere with Raf signaling (233, 234, 235) . Several staurosporine derivatives including UCN-O1, CGP41251, and PKC412 are able to inhibit PKC signaling, and have been examined in cell lines and clinical studies (149 , 150 , 236) . Aberrant MEK and ERK activity has been demonstrated in AML and CML (237, 238, 239, 240) , and MEK inhibitors such as PD098059, PD184352, and UO126 are able to modulate cellular proliferation, differentiation, and apoptosis (241, 242, 243) . PD184352 has been examined in Phase I trials in patients (244) . Pharmacological inhibitors of PI3K, wortmannin, and LY294002 have shown significant potency in preclinical studies (245 , 246) .

Fig. 4.
Fig. 4.

Targets for inhibition in RTK signaling pathways.

Downstream targets of these signaling pathways involved in cell-cycle regulation, cell survival, and apoptosis can also be modulated (Table 1)⇓ . For examples, agents capable of promoting apoptosis are being developed (247) . These may function by activating the caspase cascade through blockade of the IAPs, inhibition of the NFκB pathway (using IκB kinase inhibitors or proteasome inhibitors), and inhibition of the PI3K pathway (using kinase inhibitors; Refs. 69 , 134 , 248 ). IAPs including the XIAP can block the process of programmed cell death through their interaction with members of the caspase family of cysteine proteases (249) . The human family of caspases includes 11 members involved in processing of inflammatory cytokines as well as execution of apoptosis (250) . Dysregulation of caspase cascade has been implicated in human neoplasia, and IAPs, the natural inhibitors of caspases, are pivotal in this regulatory process (250 , 251) . XIAP, the most potent member of the IAP family blocks both the initiator caspase-9, and the effector caspases-3 and -7 (252) . An association between XIAP levels and survival has been reported in AML (253) . Down-regulation of XIAP protein by adenoviral antisense vector results in sensitization to radiation-induced cell death (254) .

View this table:
Table 1

Targets for drug development

The ubiquitin-proteasome pathway is the central pathway for degradation of intracellular proteins (255 , 256) . Targeting of proteins to proteasome is through covalent attachment of a poly-ubiquitin chain. This system is specific allowing up-regulation of degradation of certain proteins without affecting the proteolysis of other substrates; this enables the proteasome to function as a regulator of metabolic pathways (256) . Therefore, different classes of proteasome inhibitors can be used to differentially affect cellular levels of oncogenic proteins (256) . Important substrates for proteasome degradation include cyclins and CDKIs; transcription factors such as p53, NFκB, c-Myc, c-fos, and c-Jun; a number of apoptosis family of proteins; IAPs; and some caspases (256, 257, 258, 259, 260, 261, 262) . PS-341 is a specific and potent inhibitor of proteasome (263) . It induces apoptosis and overcomes resistance in a number of cell lines as well as primary cells from patients with chronic lymphocytic leukemia (264, 265, 266, 267, 268) . Its in vitro activity in myeloma has led to its ongoing examination in clinical trials (269, 270, 271) .

Cell-cycle proteins such as the CDKs and their inhibitors (CDKIs), which modulate cell-cycle progression in response to appropriate signals, are also possible targets. Orderly cell division requires a tight control of cyclins and CDKs, particularly at the G1/S checkpoint (272) . Complexes of Rb family of tumor suppressors with E2F transcription factors inhibit the transcription of several genes involved in the S phase of cell cycle both by active repression as well as through the recruitment of HDACs (273 , 274) . Phosphorylation of Rb by cyclin/CDK complexes leads to release of E2Fs and transactivation of target genes by binding of E2Fs to E2F response elements (275) . The activity of cyclin D:CDK4/6 and cyclin E:CDK2 complexes is regulated by CDKIs of the INK4 and KIP families such as p16ink4a, p15ink4b, p18ink4c, p19ink4d, p21waf1/cip1, p27kip1, and p57kip2, which act as inhibitors of G1/S transition. Disrupted activity of a number of G1 checkpoint genes/proteins has been implicated in carcinogenesis (275) . Decreased Rb expression, and a negative correlation between Rb expression and survival have been reported in ALL (276) . Deletions and mutations of Rb have been reported in a number of hematological malignancies (276) . Genes for p16ink4a and p15ink4b are suppressed in various hematological cancers mainly by deletion and by hypermethyl-ation of their promoters (277 , 278) . The role of inactivation of these genes as a prognostic indicator has been controversial (275) . Alternatively, oncogenic amplification, and overexpression of cyclins and CDKs have been reported in a number of hematological cancers (279) . Of note are overexpression of cyclin D1 in mantle cell lymphoma and hyperactivation of cdk4/cdk6 in human T-cell leukemia virus type 1 leukemias (279) . Inhibitors of cyclins and CDKs such as flavopiridol, and the staurosporine derivative UCN-01 are under active development (248 , 280) . Early phase clinical trials of these agents have been reported recently (279 , 281) . However, it is likely that the majority these drugs will be used in combination with standard cytotoxic chemotherapy agents or for therapy of minimal residual disease.

Concluding Remarks

Over the past decade extensive research has elucidated the role of cellular signaling pathways in cellular growth, differentiation, and apoptosis. The disruption of these pathways, on the other hand, has been shown to promote the neoplastic transformation of cells. This knowledge has led to the development of a number of molecules that in preclinical and clinical studies have been shown to be capable of reversing the neoplastic process. Our current challenge is to further understand the complexity of these processes and to devise specific agents that target the neoplastic cells whereas sparing normal tissues. This would truly realize the concept of targeted therapy in treating hematological malignancies and solid tumors alike.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • ↵1 To whom requests for reprints should be addressed, at University of Illinois—Chicago, 840 South Wood Street, MC 787 Chicago, IL 60612-7323. Phone: (312) 996-5982; Fax: (312) 413-4131; E-mail: ravandi{at}uic.edu

  • ↵2 The abbreviations used are: TK, tyrosine kinase; Jak, janus kinase; Stat, signal transducer and activator of transcription; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; IL, interleukin; GM-CSF, granulocyte macrophage colony-stimulating factor; JNK, c-Jun NH2-terminal kinase; SAPK, stress-activated protein kinase; PKB, protein kinase B; PI3K, phosphatidylinositol 3′-kinase; PDGFR, platelet-derived growth factor receptor; TNF, tumor necrosis factor; SHP-1, SH-2 domain containing protein tyrosine phosphatase-1; SOCS, suppressor of cytokine signaling; PIAS, protein inhibitor of activated stat; RTK, receptor tyrosine kinase; FLT3R, FMS-like tyrosine kinase 3 receptor; Grb2, growth factor receptor binding protein 2; RSK, ribosomal S6 kinase; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia; ALL, acute lymphoblastic leukemia; MEK, mitogen-activated protein/extracellular signal-regulated kinase kinase; ALK, anaplastic lymphoma kinase; NPM, nucleophosmin; ATRA, all-trans-retinoic acid; APL, acute promyelocytic leukemia; NFκB, nuclear factor κB; IκB, inhibitor of nuclear factor-κB; HDAC, histone deacetylase; IAP, inhibitor of apoptotic pathway; CDK, cyclin-dependent kinase; CDKI, cyclin-dependent kinase inhibitor; Rb, retinoblastoma; RAR, retinoic acid receptor; XIAP, X-linked inhibitor of apoptosis.

  • Received June 25, 2002.
  • Revision received September 5, 2002.
  • Accepted September 6, 2002.

References

  1. ↵
    Alberts B., Bray D., Lewis J., Raff M., Roberts K., Watson J. D. Molecular Biology of the Cell Ed. 3 721-785, Garland Publishing Inc. New York, London 1994.
  2. ↵
    Kishimoto T. The biology of interleukin-6. Blood, 74: 1-10, 1989.
    OpenUrlFREE Full Text
  3. ↵
    Rane S. G., Reddy E. P. JAKs. STATs and Src kinases in hematopoiesis. Oncogene, 21: 3334-3358, 2002.
    OpenUrlCrossRefPubMed
  4. ↵
    Shuai K. The STAT family of proteins in cytokine signaling. Prog. Biophys. Mol. Biol., 71: 405-422, 1999.
    OpenUrlCrossRefPubMed
  5. ↵
    Ihle J. N., Thierfelder W., Teglund S., Stravapodis D., Wang D., Feng J., Parganas E. Signaling by the cytokine receptor superfamily. Ann. N. Y. Acad. Sci., 865: 1-9, 1998.
    OpenUrlCrossRefPubMed
  6. ↵
    Darnell J. E., Jr., Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science (Wash. DC), 264: 1415-1421, 1994.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Decker T., Kovarik P. Transcription factor activity of STAT proteins: structural requirements and regulation by phosphorylation and interacting proteins. Cell Mol. Life Sci., 55: 1535-1546, 1999.
    OpenUrlCrossRefPubMed
  8. ↵
    Cooper J. A., Howell B. The when and how of Src regulation. Cell, 73: 1051-1054, 1993.
    OpenUrlCrossRefPubMed
  9. ↵
    Pawson T. Protein modules and signalling networks. Nature (Lond.), 373: 573-580, 1995.
    OpenUrlCrossRefPubMed
  10. ↵
    McCubrey J. A., May W. S., Duronio V., Mufson A. Serine/threonine phosphorylation in cytokine signal transduction. Leukemia (Baltimore), 14: 9-21, 2000.
    OpenUrlCrossRefPubMed
  11. ↵
    Pratt J. C., Weiss M., Sieff C. A., Shoelson S. E., Burakoff S. J., Ravichandran K. S. Evidence for a physical association between the Shc-PTB domain and the β c chain of the granulocyte-macrophage colony-stimulating factor receptor. J. Biol. Chem., 271: 12137-12140, 1996.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Okuda K., Sanghera J. S., Pelech S. L., Kanakura Y., Hallek M., Griffin J. D., Druker B. J. Granulocyte-macrophage colony-stimulating factor, interleukin-3, and steel factor induce rapid tyrosine phosphorylation of p42 and p44 MAP kinase. Blood, 79: 2880-2887, 1992.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Coffer P. J., Geijsen N., M’Rabet L., Schweizer R. C., Maikoe T., Raaijmakers J. A., Lammers J. W., Koenderman L. Comparison of the roles of mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signal transduction in neutrophil effector function. Biochem. J., 329: 121-130, 1998.
  14. ↵
    Itoh T., Muto A., Watanabe S., Miyajima A., Yokota T., Arai K. Granulocyte-macrophage colony-stimulating factor provokes RAS activation and transcription of c-fos through different modes of signaling. J. Biol. Chem., 271: 7587-7592, 1996.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Nagata Y., Moriguchi T., Nishida E., Todokoro K. Activation of p38 MAP kinase pathway by erythropoietin and interleukin- 3. Blood, 90: 929-934, 1997.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Nagata Y., Nishida E., Todokoro K. Activation of JNK signaling pathway by erythropoietin, thrombopoietin, and interleukin-3. Blood, 89: 2664-2669, 1997.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Foltz I. N., Schrader J. W. Activation of the stress-activated protein kinases by multiple hematopoietic growth factors with the exception of interleukin-4. Blood, 89: 3092-3096, 1997.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Terada K., Kaziro Y., Satoh T. Ras-dependent activation of c-Jun N-terminal kinase/stress-activated protein kinase in response to interleukin-3 stimulation in hematopoietic BaF3 cells. J. Biol. Chem., 272: 4544-4548, 1997.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Coffer P. J., Schweizer R. C., Dubois G. R., Maikoe T., Lammers J. W., Koenderman L. Analysis of signal transduction pathways in human eosinophils activated by chemoattractants and the T-helper 2-derived cytokines interleukin-4 and interleukin-5. Blood, 91: 2547-2557, 1998.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Tilton B., Andjelkovic M., Didichenko S. A., Hemmings B. A., Thelen M. G-Protein-coupled receptors and Fcγ-receptors mediate activation of Akt/protein kinase B in human phagocytes. J. Biol. Chem., 272: 28096-28101, 1997.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Songyang Z., Baltimore D., Cantley L. C., Kaplan D. R., Franke T. F. Interleukin 3-dependent survival by the Akt protein kinase. Proc. Natl. Acad. Sci. USA, 94: 11345-11350, 1997.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Sato N., Sakamaki K., Terada N., Arai K., Miyajima A. Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common β subunit responsible for different signaling. EMBO J., 12: 4181-4189, 1993.
    OpenUrlPubMed
  23. ↵
    Calvo V., Wood M., Gjertson C., Vik T., Bierer B. E. Activation of 70-kDa S6 kinase, induced by the cytokines interleukin-3 and erythropoietin and inhibited by rapamycin, is not an absolute requirement for cell proliferation. Eur. J. Immunol., 24: 2664-2671, 1994.
    OpenUrlCrossRefPubMed
  24. ↵
    Scheijen B., Griffin J. D. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene, 21: 3314-3333, 2002.
    OpenUrlCrossRefPubMed
  25. ↵
    Frank D. A. STAT signaling in the pathogenesis and treatment of cancer. Mol. Med., 5: 432-456, 1999.
    OpenUrlPubMed
  26. ↵
    Metcalf D. The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature (Lond.), 339: 27-30, 1989.
    OpenUrlCrossRefPubMed
  27. ↵
    Taniguchi T. Cytokine signaling through non-receptor protein tyrosine kinase. Science (Wash. DC), 268: 251-255, 1995.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Hunter T. Signal transduction. Cytokine connections. Nature (Lond.), 366: 114-116, 1993.
    OpenUrlCrossRefPubMed
  29. ↵
    Stahl N., Yancopoulos G. D. The αs, βs, and kinases of cytokine receptor complexes. Cell, 74: 587-590, 1993.
    OpenUrlCrossRefPubMed
  30. ↵
    Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell, 76: 253-262, 1994.
    OpenUrlCrossRefPubMed
  31. ↵
    Carpenter L., Yancopoulos G., Stahl N. General mechanisms of cytokine receptor signaling. Adv. Protein Chem., 52: 109-140, 1999.
    OpenUrl
  32. ↵
    Kobayashi N., Kono T., Hatakeyama M., Minami Y., Miyazaki T., Perlmutter R. M., Taniguchi T. Functional coupling of the src-family of kinases p59fyn and p53/56lyn with the interleukin 2 receptor: Implications for redundancy and pleiotropism in cytokine signal transduction. Proc. Natl. Acad. Sci. USA, 90: 4201-4205, 1993.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    Yeh T. C., Pellegrini S. The Janus kinase family of protein tyrosine kinases and their role in signaling. Cell. Mol. Life Sci., 55: 1523-1534, 1999.
    OpenUrlCrossRefPubMed
  34. ↵
    Ward A. C., Touw I., Yoshimura A. The Jak-Stat pathway in normal and perturbed hematopoieis. Blood, 95: 19-29, 2000.
    OpenUrlFREE Full Text
  35. ↵
    Zhao Y., Wagner F., Frank S. J., Kraft A. S. The amino-terminal portion of the JAK2 protein kinase is necessary for binding and phosphorylation of the granulocyte-macrophage colony- stimulating factor receptor β c chain. J. Biol. Chem., 270: 13814-13818, 1995.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Saharinen P., Takaluoma K., Silvennoinen O. Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol. Cell. Biol., 20: 3387-3395, 2000.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    Livnah O., Stura E. A., Middleton S. A., Johnson D. L., Jolliffe L. K., Wilson I. A. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science (Wash. DC), 283: 987-990, 1999.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Remy I., Wilson I. A., Michnick S. W. Erythropoietin receptor activation by a ligand-induced conformation change. Science (Wash. DC), 283: 990-993, 1999.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Duhe R. J., Farrar W. L. Characterization of active and inactive forms of the JAK2 protein- tyrosine kinase produced via the baculovirus expression vector system. J. Biol. Chem., 270: 23084-23089, 1995.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Zhou Y. J., Hanson E. P., Chen Y. Q., Magnuson K., Chen M., Swann P. G., Wange R. L., Changelian P. S., O’Shea J. J. Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity. Proc. Natl. Acad. Sci. USA, 94: 13850-13855, 1997.
    OpenUrlAbstract/FREE Full Text
  41. ↵
    Notarangelo L. D. Immunodeficiencies caused by genetic defects in protein kinases. Curr. Opin. Immunol., 8: 448-453, 1996.
    OpenUrlCrossRefPubMed
  42. ↵
    Lacronique V., Boureux A., Valle V. D., Poirel H., Quang C. T., Mauchauffe M., Berthou C., Lessard M., Berger R., Ghysdael J., Bernard O. A. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science (Wash. DC), 278: 1309-1312, 1997.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    Peeters P., Raynaud S. D., Cools J., Wlodarska I., Grosgeorge J., Philip P., Monpoux F., Van Rompaey L., Baens M., Van den Berghe H., Marynen P. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor- associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood, 90: 2535-2540, 1997.
    OpenUrlAbstract/FREE Full Text
  44. ↵
    Migone T. S., Lin J. X., Cereseto A., Mulloy J. C., O’Shea J. J., Franchini G., Leonard W. J. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science (Wash. DC), 269: 79-81, 1995.
    OpenUrlAbstract/FREE Full Text
  45. ↵
    Danial N. N., Pernis A., Rothman P. B. Jak-STAT signaling induced by the v-abl oncogene. Science (Wash. DC), 269: 1875-1877, 1995.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    Darnell J. E., Jr. STATs and gene regulation. Science (Wash. DC), 277: 1630-1635, 1997.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    Fu X. Y., Schindler C., Improta T., Aebersold R., Darnell J. E., Jr. The proteins of ISGF-3, the interferon α-induced transcriptional activator, define a gene family involved in signal transduction, Proc. Natl. Acad. Sci. USA, 89: 7840-7843, 1992.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    Khan K. D., Shuai K., Lindwall G., Maher S. E., Darnell J. E., Jr., Bothwell A. L. Induction of the Ly-6A/E gene by interferon α/β and γ requires a DNA element to which a tyrosine-phosphorylated 91-kDa protein binds. Proc. Natl. Acad. Sci. USA, 90: 6806-6810, 1993.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    Shuai K., Schindler C., Prezioso V. R., Darnell J. E., Jr. Activation of transcription by IFN-γ: tyrosine phosphorylation of a 91-kD DNA binding protein. Science (Wash. DC), 258: 1808-1812, 1992.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    Shuai K., Stark G. R., Kerr I. M., Darnell J. E., Jr. A single phosphotyrosine residue of Stat91 required for gene activation by interferon-γ. Science (Wash. DC), 261: 1744-1746, 1993.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    Zhong Z., Wen Z., Darnell J. E., Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science (Wash. DC), 264: 95-98, 1994.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    Shuai K., Horvath C. M., Huang L. H., Qureshi S. A., Cowburn D., Darnell J. E., Jr. Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell, 76: 821-828, 1994.
    OpenUrlCrossRefPubMed
  53. ↵
    Kohlhuber F., Rogers N. C., Watling D., Feng J., Guschin D., Briscoe J., Witthuhn B. A., Kotenko S. V., Pestka S., Stark G. R., Ihle J. N., Kerr I. M. A JAK1/JAK2 chimera can sustain α and γ interferon responses. Mol. Cell. Biol., 17: 695-706, 1997.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    Kotenko S. V., Izotova L. S., Pollack B. P., Muthukumaran G., Paukku K., Silvennoinen O., Ihle J. N., Pestka S. Other kinases can substitute for Jak2 in signal transduction by interferon-γ. J. Biol. Chem., 271: 17174-17182, 1996.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    Bhattacharya S., Eckner R., Grossman S., Oldread E., Arany Z., D’Andrea A., Livingston D. M. Cooperation of Stat2 and p300/CBP in signalling induced by interferon- α. Nature (Lond.), 383: 344-347, 1996.
    OpenUrlCrossRefPubMed
  56. ↵
    Horvai A. E., Xu L., Korzus E., Brard G., Kalafus D., Mullen T. M., Rose D. W., Rosenfeld M. G., Glass C. K. Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300. Proc. Natl. Acad. Sci. USA, 94: 1074-1079, 1997.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    Eilers A., Georgellis D., Klose B., Schindler C., Ziemiecki A., Harpur A. G. Differentiation-regulated serine phosphorylation of STAT1 promotes GAF activation in macrophages. Mol. Cell. Biol., 15: 3579-3586, 1995.
    OpenUrlAbstract/FREE Full Text
  58. ↵
    Schindler C. STATs as activators of apoptosis. Trends Cell Biol., 8: 97-98, 1998.
    OpenUrlCrossRefPubMed
  59. ↵
    Mui A. L. The role of STATs in proliferation, differentiation, and apoptosis. Cell Mol. Life Sci., 55: 1547-1458, 1999.
    OpenUrlCrossRefPubMed
  60. ↵
    Chin Y. E., Kitagawa M., Su W. C., You Z. H., Iwamoto Y., Fu X. Y. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science (Wash. DC), 272: 719-722, 1996.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    Mui A. L., Wakao H., Kinoshita T., Kitamura T., Miyajima A. Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation. EMBO J., 15: 2425-2433, 1996.
    OpenUrlPubMed
  62. ↵
    O’Farrell A. M., Liu Y., Moore K. W., Mui A. L. IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways. EMBO J., 17: 1006-1018, 1998.
    OpenUrlAbstract
  63. ↵
    Chaturvedi P., Reddy M. V., Reddy E. P. Src kinases and not JAKs activate STATs during IL-3 induced myeloid cell proliferation. Oncogene, 16: 1749-1758, 1998.
    OpenUrlCrossRefPubMed
  64. ↵
    Kumar A., Commane M., Flickinger T. W., Horvath C. M., Stark G. R. Defective TNF-α-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science (Wash. DC), 278: 1630-1632, 1997.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Zamorano J., Keegan A. D. Regulation of apoptosis by tyrosine-containing domains of IL-4R α: Y497 and Y713, but not the STAT6-docking tyrosines, signal protection from apoptosis. J. Immunol., 161: 859-867, 1998.
    OpenUrlAbstract/FREE Full Text
  66. ↵
    Fukada T., Hibi M., Yamanaka Y., Takahashi-Tezuka M., Fujitani Y., Yamaguchi T., Nakajima K., Hirano T. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity, 5: 449-460, 1996.
    OpenUrlCrossRefPubMed
  67. ↵
    Xu X., Fu X. Y., Plate J., Chong A. S. IFN-γ induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression. Cancer Res., 58: 2832-2837, 1998.
    OpenUrlAbstract/FREE Full Text
  68. ↵
    Kim T. K., Maniatis T. Regulation of interferon-γ-activated STAT1 by the ubiquitin- proteasome pathway. Science (Wash. DC), 273: 1717-1719, 1996.
    OpenUrlAbstract/FREE Full Text
  69. ↵
    An W. G., Hwang S. G., Trepel J. B., Blagosklonny M. V. Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia (Baltimore), 14: 1276-1283, 2000.
    OpenUrlCrossRefPubMed
  70. ↵
    Starr R., Hilton D. J. Negative regulation of the Jak/Stat pathway. Bioassays, 21: 47-52, 1999.
    OpenUrlCrossRefPubMed
  71. ↵
    Hilton D. J. Negative regulators of cytokine signal transduction. Cell Mol. Life Sci., 55: 1568-1577, 1999.
    OpenUrlCrossRefPubMed
  72. ↵
    Jiao H., Yang W., Berrada K., Tabrizi M., Shultz L., Yi T. Macrophages from motheaten and viable motheaten mutant mice show increased proliferative responses to GM-CSF: detection of potential HCP substrates in GM-CSF signal transduction. Exp. Hematol., 25: 592-600, 1997.
    OpenUrlPubMed
  73. ↵
    Alexander W. S., Starr R., Metcalf D., Nicholson S. E., Farley A., Elefanty A. G., Brysha M., Kile B. T., Richardson R., Baca M., Zhang J. G., Willson T. A., Viney E. M., Sprigg N. S., Rakar S., Corbin J., Mifsud S., DiRago L., Cary D., Nicola N. A., Hilton D. J. Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction. J. Leukoc. Biol., 66: 588-592, 1999.
    OpenUrlAbstract
  74. ↵
    Nicholson S. E., Willson T. A., Farley A., Starr R., Zhang J. G., Baca M., Alexander W. S., Metcalf D., Hilton D. J., Nicola N. A. Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J., 18: 375-385, 1999.
    OpenUrlAbstract
  75. ↵
    Adams T. E., Hansen J. A., Starr R., Nicola N. A., Hilton D. J., Billestrup N. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling. J. Biol. Chem., 273: 1285-1287, 1998.
    OpenUrlAbstract/FREE Full Text
  76. ↵
    Song M. M., Shuai K. The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J. Biol. Chem., 273: 35056-35062, 1998.
    OpenUrlAbstract/FREE Full Text
  77. ↵
    Schultheis B., Carapeti-Marootian M., Hochhaus A., Weisser A., Goldman J. M., Melo J. V. Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism. Blood, 99: 1766-1775, 2002.
    OpenUrlAbstract/FREE Full Text
  78. ↵
    Porter A. C., Vaillancourt R. R. Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. Oncogene, 17: 1343-1352, 1998.
    OpenUrlCrossRefPubMed
  79. ↵
    Drexler H. G. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia (Baltimore), 10: 588-599, 1996.
    OpenUrlPubMed
  80. ↵
    Blume-Jensen P., Hunter T. Oncogenic kinase signalling. Nature (Lond.), 411: 355-365, 2001.
    OpenUrlCrossRefPubMed
  81. ↵
    Weiss F. U., Daub H., Ullrich A. Novel mechanisms of RTK signal generation. Curr. Opin. Genet. Dev., 7: 80-86, 1997.
    OpenUrlCrossRefPubMed
  82. ↵
    Weiss A., Schlessinger J. Switching signals on or off by receptor dimerization. Cell, 94: 277-280, 1998.
    OpenUrlCrossRefPubMed
  83. ↵
    Sherr C. J. Colony-stimulating factor-1 receptor. Blood, 75: 1-12, 1990.
    OpenUrlFREE Full Text
  84. ↵
    Matthews W., Jordan C. T., Wiegand G. W., Pardoll D., Lemischka I. R. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell, 65: 1143-1152, 1991.
    OpenUrlCrossRefPubMed
  85. ↵
    Tse K. F., Mukherjee G., Small D. Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia (Baltimore), 14: 1766-1776, 2000.
    OpenUrlCrossRefPubMed
  86. ↵
    Gilliland D. G., Griffin J. D. The roles of FLT3 in hematopoiesis and leukemia. Blood, 100: 1532-1542, 2002.
    OpenUrlAbstract/FREE Full Text
  87. ↵
    Thiede C., Steudel C., Mohr B., Schaich M., Schakel U., Platzbecker U., Wermke M., Bornhauser M., Ritter M., Neubauer A., Ehninger G., Illmer T. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 99: 4326-4335, 2002.
    OpenUrlAbstract/FREE Full Text
  88. ↵
    Gilliland D. G., Griffin J. D. Role of FLT3 in leukemia. Curr. Opin. Hematol., 9: 274-281, 2002.
    OpenUrlCrossRefPubMed
  89. ↵
    Kiyoi H., Ohno R., Ueda R., Saito H., Naoe T. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene, 21: 2555-2563, 2002.
    OpenUrlCrossRefPubMed
  90. ↵
    Kelly L. M., Liu Q., Kutok J. L., Williams I. R., Boulton C. L., Gilliland D. G. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood, 99: 310-318, 2002.
    OpenUrlAbstract/FREE Full Text
  91. ↵
    Yamamoto Y., Kiyoi H., Nakano Y., Suzuki R., Kodera Y., Miyawaki S., Asou N., Kuriyama K., Yagasaki F., Shimazaki C., Akiyama H., Saito K., Nishimura M., Motoji T., Shinagawa K., Takeshita A., Saito H., Ueda R., Ohno R., Naoe T. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood, 97: 2434-2439, 2001.
    OpenUrlAbstract/FREE Full Text
  92. ↵
    Levis M., Tse K. F., Smith B. D., Garrett E., Small D. A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood, 98: 885-887, 2001.
    OpenUrlAbstract/FREE Full Text
  93. ↵
    Levis M., Allebach J., Tse K. F., Zheng R., Baldwin B. R., Smith B. D., Jones-Bolin S., Ruggeri B., Dionne C., Small D. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood, 99: 3885-3891, 2002.
    OpenUrlAbstract/FREE Full Text
  94. ↵
    Schwartzberg P. L. The many faces of Src: multiple functions of a prototypical tyrosine kinase. Oncogene, 17: 1463-1468, 1998.
    OpenUrlCrossRefPubMed
  95. ↵
    Lee J. T., Jr., McCubrey J. A. The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia. Leukemia (Baltimore), 16: 486-507, 2002.
    OpenUrlCrossRefPubMed
  96. ↵
    Beaupre D. M., Kurzrock R. RAS and leukemia: from basic mechanisms to gene-directed therapy. J. Clin. Oncol., 17: 1071-1079, 1999.
    OpenUrlAbstract/FREE Full Text
  97. ↵
    Campbell S. L., Khosravi-Far R., Rossman K. L., Clark G. J., Der C. J. Increasing complexity of Ras signaling. Oncogene, 17: 1395-1413, 1998.
    OpenUrlCrossRefPubMed
  98. ↵
    Prendergast G. C., Gibbs J. B. Ras regulatory interactions: novel targets for anti-cancer intervention?. Bioessays, 16: 187-191, 1994.
    OpenUrlCrossRefPubMed
  99. ↵
    Crews C. M., Erikson R. L. Extracellular signals and reversible protein phosphorylation: what to Mek of it all. Cell, 74: 215-217, 1993.
    OpenUrlPubMed
  100. ↵
    Crews C. M., Alessandrini A., Erikson R. L. Erks: their fifteen minutes has arrived. Cell Growth Differ., 3: 135-142, 1992.
    OpenUrlAbstract
  101. ↵
    Dhanasekaran N., Premkumar Reddy E. Signaling by dual specificity kinases. Oncogene, 17: 1447-1455, 1998.
    OpenUrlCrossRefPubMed
  102. ↵
    Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell, 73: 381-393, 1993.
    OpenUrlCrossRefPubMed
  103. ↵
    Boulton T. G., Nye S. H., Robbins D. J., Ip N. Y., Radziejewska E., Morgenbesser S. D., DePinho R. A., Panayotatos N., Cobb M. H., Yancopoulos G. D. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell, 65: 663-675, 1991.
    OpenUrlCrossRefPubMed
  104. ↵
    Nebreda A. R., Gavin A. C. Perspectives: signal transduction. Cell survival demands some Rsk. Science (Wash. DC), 286: 1309-1310, 1999.
    OpenUrlFREE Full Text
  105. ↵
    Bonni A., Brunet A., West A. E., Datta S. R., Takasu M. A., Greenberg M. E. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science (Wash. DC), 286: 1358-1362, 1999.
    OpenUrlAbstract/FREE Full Text
  106. ↵
    Kerkhoff E., Rapp U. R. Cell cycle targets of Ras/Raf signalling. Oncogene, 17: 1457-1462, 1998.
    OpenUrlCrossRefPubMed
  107. ↵
    Sherr C. J. Growth factor-regulated G1 cyclins. Stem Cells, 12: 47-57, 1994.
  108. ↵
    Mayol X., Grana X. pRB, p107 and p130 as transcriptional regulators: role in cell growth and differentiation. Prog. Cell Cycle Res., 3: 157-169, 1997.
    OpenUrlPubMed
  109. ↵
    Dimri G. P., Nakanishi M., Desprez P. Y., Smith J. R., Campisi J. Inhibition of E2F activity by the cyclin-dependent protein kinase inhibitor p21 in cells expressing or lacking a functional retinoblastoma protein. Mol. Cell. Biol., 16: 2987-2997, 1996.
    OpenUrlAbstract/FREE Full Text
  110. ↵
    Steinman R. A. Cell cycle regulators and hematopoiesis. Oncogene, 21: 3403-3413, 2002.
    OpenUrlCrossRefPubMed
  111. ↵
    Jiang Y., Gram H., Zhao M., New L., Gu J., Feng L., Di Padova F., Ulevitch R. J., Han J. Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38δ. J. Biol. Chem., 272: 30122-30128, 1997.
    OpenUrlAbstract/FREE Full Text
  112. ↵
    Lechner C., Zahalka M. A., Giot J. F., Moller N. P., Ullrich A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc. Natl. Acad. Sci. USA, 93: 4355-4359, 1996.
    OpenUrlAbstract/FREE Full Text
  113. ↵
    Enslen H., Brancho D. M., Davis R. J. Molecular determinants that mediate selective activation of p38 MAP kinase isoforms. EMBO J., 19: 1301-1311, 2000.
    OpenUrlAbstract
  114. ↵
    Uddin S., Majchrzak B., Woodson J., Arunkumar P., Alsayed Y., Pine R., Young P. R., Fish E. N., Platanias L. C. Activation of the p38 mitogen-activated protein kinase by type I interferons. J. Biol. Chem., 274: 30127-30131, 1999.
    OpenUrlAbstract/FREE Full Text
  115. ↵
    Mayer I. A., Verma A., Grumbach I. M., Uddin S., Lekmine F., Ravandi F., Majchrzak B., Fujita S., Fish E. N., Platanias L. C. The p38 MAPK pathway mediates the growth inhibitory effects of interferon-α in BCR-ABL-expressing cells. J. Biol. Chem., 276: 28570-28577, 2001.
    OpenUrlAbstract/FREE Full Text
  116. ↵
    Verma A., Deb D. K., Sassano A., Uddin S., Varga J., Wickrema A., Platanias L. C. Activation of the p38 mitogen-activated protein kinase mediates the suppressive effects of type I interferons and transforming growth factor-β on normal eematopoiesis. J. Biol. Chem., 277: 7726-7735, 2002.
    OpenUrlAbstract/FREE Full Text
  117. ↵
    Ichijo H. From receptors to stress-activated MAP kinases. Oncogene, 18: 6087-6093, 1999.
    OpenUrlCrossRefPubMed
  118. ↵
    Fuchs S. Y., Adler V., Pincus M. R., Ronai Z. MEKK1/JNK signaling stabilizes and activates p53. Proc. Natl. Acad. Sci. USA, 95: 10541-10546, 1998.
    OpenUrlAbstract/FREE Full Text
  119. ↵
    Keyse S. M. Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr. Opin. Cell Biol., 12: 186-192, 2000.
    OpenUrlCrossRefPubMed
  120. ↵
    Camps M., Nichols A., Gillieron C., Antonsson B., Muda M., Chabert C., Boschert U., Arkinstall S. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science (Wash. DC), 280: 1262-1265, 1998.
    OpenUrlAbstract/FREE Full Text
  121. ↵
    Camps M., Nichols A., Arkinstall S. Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J., 14: 6-16, 2000.
    OpenUrlAbstract/FREE Full Text
  122. ↵
    Chung H., Brautigan D. L. Protein phosphatase 2A suppresses MAP kinase signalling and ectopic protein expression. Cell Signalling, 11: 575-580, 1999.
    OpenUrlCrossRefPubMed
  123. ↵
    Wassarman D. A., Solomon N. M., Chang H. C., Karim F. D., Therrien M., Rubin G. M. Protein phosphatase 2A positively and negatively regulates Ras1- mediated photoreceptor development in Drosophila. Genes Dev., 10: 272-278, 1996.
    OpenUrlAbstract/FREE Full Text
  124. ↵
    Klippel A., Escobedo J. A., Fantl W. J., Williams L. T. The C-terminal SH2 domain of p85 accounts for the high affinity and specificity of the binding of phosphatidylinositol 3-kinase to phosphorylated platelet-derived growth factor β receptor. Mol. Cell. Biol., 12: 1451-1459, 1992.
    OpenUrlAbstract/FREE Full Text
  125. ↵
    Hiles I. D., Otsu M., Volinia S., Fry M. J., Gout I., Dhand R., Panayotou G., Ruiz-Larrea F., Thompson A., Totty N. F., et al Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell, 70: 419-429, 1992.
    OpenUrlCrossRefPubMed
  126. ↵
    Shoelson S. E., Sivaraja M., Williams K. P., Hu P., Schlessinger J., Weiss M. A. Specific phosphopeptide binding regulates a conformational change in the PI 3-kinase SH2 domain associated with enzyme activation. EMBO J., 12: 795-802, 1993.
    OpenUrlPubMed
  127. ↵
    Anderson K. E., Coadwell J., Stephens L. R., Hawkins P. T. Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B. Curr. Biol., 8: 684-691, 1998.
    OpenUrlCrossRefPubMed
  128. ↵
    Scheid M. P., Duronio V. Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation. Proc. Natl. Acad. Sci. USA, 95: 7439-7444, 1998.
    OpenUrlAbstract/FREE Full Text
  129. ↵
    del Peso L., Gonzalez-Garcia M., Page C., Herrera R., Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science (Wash. DC), 278: 687-689, 1997.
    OpenUrlAbstract/FREE Full Text
  130. ↵
    Datta S. R., Dudek H., Tao X., Masters S., Fu H., Gotoh Y., Greenberg M. E. Akt phosphorylation of BAD couples survival signals to the cell- intrinsic death machinery. Cell, 91: 231-241, 1997.
    OpenUrlCrossRefPubMed
  131. ↵
    Khwaja A. Akt is more than just a Bad kinase. Nature (Lond.), 401: 33-34, 1999.
    OpenUrlCrossRefPubMed
  132. ↵
    Dong F., Larner A. C. Activation of Akt kinase by granulocyte colony-stimulating factor (G-CSF): evidence for the role of a tyrosine kinase activity distinct from the Janus kinases. Blood, 95: 1656-1662, 2000.
    OpenUrlAbstract/FREE Full Text
  133. ↵
    Aoki M., Batista O., Bellacosa A., Tsichlis P., Vogt P. K. The akt kinase: molecular determinants of oncogenicity. Proc. Natl. Acad. Sci. USA, 95: 14950-14955, 1998.
    OpenUrlAbstract/FREE Full Text
  134. ↵
    Sellers W. R., Fisher D. E. Apoptosis and cancer drug targeting. J. Clin. Investig., 104: 1655-1661, 1999.
    OpenUrlCrossRefPubMed
  135. ↵
    Blagosklonny M. V., Chuman Y., Bergan R. C., Fojo T. Mitogen-activated protein kinase pathway is dispensable for microtubule-active drug-induced Raf-1/Bcl-2 phosphorylation and apoptosis in leukemia cells. Leukemia (Baltimore), 13: 1028-1036, 1999.
    OpenUrlCrossRefPubMed
  136. ↵
    Pahl H. L. Activators and target genes of Rel/NF-κB transcription factors. Oncogene, 18: 6853-6866, 1999.
    OpenUrlCrossRefPubMed
  137. ↵
    Li J., Yen C., Liaw D., Podsypanina K., Bose S., Wang S. I., Puc J., Miliaresis C., Rodgers L., McCombie R., Bigner S. H., Giovanella B. C., Ittmann M., Tycko B., Hibshoosh H., Wigler M. H., Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science (Wash. DC), 275: 1943-1947, 1997.
    OpenUrlAbstract/FREE Full Text
  138. ↵
    Stambolic V., Suzuki A., de la Pompa J. L., Brothers G. M., Mirtsos C., Sasaki T., Ruland J., Penninger J. M., Siderovski D. P., Mak T. W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 95: 29-39, 1998.
    OpenUrlCrossRefPubMed
  139. ↵
    Maehama T., Dixon J. E. The tumor suppressor. PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J. Biol. Chem., 273: 13375-13378, 1998.
    OpenUrlAbstract/FREE Full Text
  140. ↵
    Myers M. P., Pass I., Batty I. H., Van der Kaay J., Stolarov J. P., Hemmings B. A., Wigler M. H., Downes C. P., Tonks N. K. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc. Natl. Acad. Sci. USA, 95: 13513-13518, 1998.
    OpenUrlAbstract/FREE Full Text
  141. ↵
    Podsypanina K., Ellenson L. H., Nemes A., Gu J., Tamura M., Yamada K. M., Cordon-Cardo C., Catoretti G., Fisher P. E., Parsons R. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl. Acad. Sci. USA, 96: 1563-1568, 1999.
    OpenUrlAbstract/FREE Full Text
  142. ↵
    Hu Z. B., Minden M. D., McCulloch E. A. Phosphorylation of BCL-2 after exposure of human leukemic cells to retinoic acid. Blood, 92: 1768-1775, 1998.
    OpenUrlAbstract/FREE Full Text
  143. ↵
    Haldar S., Basu A., Croce C. M. Bcl2 is the guardian of microtubule integrity. Cancer Res., 57: 229-233, 1997.
    OpenUrlAbstract/FREE Full Text
  144. ↵
    Asaoka Y., Nakamura S., Yoshida K., Nishizuka Y. Protein kinase C, calcium and phospholipid degradation. Trends Biochem. Sci., 17: 414-417, 1992.
    OpenUrlCrossRefPubMed
  145. ↵
    Liou H. C., Baltimore D. Regulation of the NF-κ B/rel transcription factor and I κ B inhibitor system. Curr. Opin. Cell Biol., 5: 477-487, 1993.
    OpenUrlCrossRefPubMed
  146. ↵
    Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science (Wash. DC), 258: 607-614, 1992.
    OpenUrlAbstract/FREE Full Text
  147. ↵
    Kovanen P. E., Junttila I., Takaluoma K., Saharinen P., Valmu L., Li W., Silvennoinen O. Regulation of Jak2 tyrosine kinase by protein kinase C during macrophage differentiation of IL-3-dependent myeloid progenitor cells. Blood, 95: 1626-1632, 2000.
    OpenUrlAbstract/FREE Full Text
  148. ↵
    Kolch W., Heidecker G., Kochs G., Hummel R., Vahidi H., Mischak H., Finkenzeller G., Marme D., Rapp U. R. Protein kinase C α activates RAF-1 by direct phosphorylation. Nature (Lond.), 364: 249-252, 1993.
    OpenUrlCrossRefPubMed
  149. ↵
    Seynaeve C. M., Kazanietz M. G., Blumberg P. M., Sausville E. A., Worland P. J. Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue. Mol. Pharmacol., 45: 1207-1214, 1994.
    OpenUrlAbstract
  150. ↵
    Thavasu P., Propper D., McDonald A., Dobbs N., Ganesan T., Talbot D., Braybrook J., Caponigro F., Hutchison C., Twelves C., Man A., Fabbro D., Harris A., Balkwill F. The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients. Cancer Res., 59: 3980-3984, 1999.
    OpenUrlAbstract/FREE Full Text
  151. ↵
    King W. G., Mattaliano M. D., Chan T. O., Tsichlis P. N., Brugge J. S. Phosphatidylinositol 3-kinase is required for integrin-stimulated AKT and Raf-1/mitogen-activated protein kinase pathway activation. Mol. Cell. Biol., 17: 4406-4418, 1997.
    OpenUrlAbstract/FREE Full Text
  152. ↵
    Wennstrom S., Downward J. Role of phosphoinositide 3kinase in activation of ras and mitogen- activated protein kinase by epidermal growth factor. Mol. Cell. Biol., 19: 4279-4288, 1999.
    OpenUrlAbstract/FREE Full Text
  153. ↵
    McCubrey J. A., Lee J. T., Steelman L. S., Blalock W. L., Moye P. W., Chang F., Pearce M., Shelton J. G., White M. K., Franklin R. A., Pohnert S. C. Interactions between the PI3K and Raf signaling pathways can result in the transformation of hematopoietic cells. Cancer Detect. Prev., 25: 375-393, 2001.
    OpenUrlPubMed
  154. ↵
    Platanias L. C., Fish E. N. Signaling pathways activated by interferons. Exp. Hematol., 27: 1583-1592, 1999.
    OpenUrlCrossRefPubMed
  155. ↵
    David M., Petricoin E., 3rd, Benjamin C., Pine R., Weber M. J., Larner A. C. Requirement for MAP kinase (ERK2) activity in interferon α- and interferon β-stimulated gene expression through STAT proteins. Science (Wash. DC), 269: 1721-1723, 1995.
    OpenUrlAbstract/FREE Full Text
  156. ↵
    Dickens M., Rogers J. S., Cavanagh J., Raitano A., Xia Z., Halpern J. R., Greenberg M. E., Sawyers C. L., Davis R. J. A cytoplasmic inhibitor of the JNK signal transduction pathway. Science (Wash. DC), 277: 693-696, 1997.
    OpenUrlAbstract/FREE Full Text
  157. ↵
    Sawyers C. L., McLaughlin J., Witte O. N. Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene. J. Exp. Med., 181: 307-313, 1995.
    OpenUrlAbstract/FREE Full Text
  158. ↵
    Skorski T., Kanakaraj P., Nieborowska-Skorska M., Ratajczak M. Z., Wen S. C., Zon G., Gewirtz A. M., Perussia B., Calabretta B. Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood, 86: 726-736, 1995.
    OpenUrlAbstract/FREE Full Text
  159. ↵
    Oda T., Heaney C., Hagopian J. R., Okuda K., Griffin J. D., Druker B. J. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J. Biol. Chem., 269: 22925-22928, 1994.
    OpenUrlAbstract/FREE Full Text
  160. ↵
    Ilaria R. L., Jr., Van Etten R. A. P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J. Biol. Chem., 271: 31704-31710, 1996.
    OpenUrlAbstract/FREE Full Text
  161. ↵
    Pendergast A. M., Quilliam L. A., Cripe L. D., Bassing C. H., Dai Z., Li N., Batzer A., Rabun K. M., Der C. J., Schlessinger J., et al BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell, 75: 175-185, 1993.
    OpenUrlCrossRefPubMed
  162. ↵
    Tauchi T., Miyazawa K., Feng G. S., Broxmeyer H. E., Toyama K. A coiled-coil tetramerization domain of BCR-ABL is essential for the interactions of SH2-containing signal transduction molecules. J. Biol. Chem., 272: 1389-1394, 1997.
    OpenUrlAbstract/FREE Full Text
  163. ↵
    Salgia R., Sattler M., Pisick E., Li J. L., Griffin J. D. p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl. Exp. Hematol., 24: 310-313, 1996.
    OpenUrlPubMed
  164. ↵
    Levitzki A., Gazit A. Tyrosine kinase inhibition: an approach to drug development. Science (Wash. DC), 267: 1782-1788, 1995.
    OpenUrlAbstract/FREE Full Text
  165. ↵
    Levitzki A. Tyrphostins: tyrosine kinase blockers as novel antiproliferative agents and directors of signal transduction. FASEB J., 6: 3275-3282, 1992.
    OpenUrlAbstract
  166. ↵
    Sawyers C. L., Druker B. Tyrosine kinase inhibitors in chronic myeloid leukemia. Cancer J. Sci. Am., 5: 63-69, 1998.
  167. ↵
    Druker B. J., Talpaz M., Resta D. J., Peng B., Buchdunger E., Ford J. M., Lydon N. B., Kantarjian H., Capdeville R., Ohno-Jones S., Sawyers C. L. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med., 344: 1031-1037, 2001.
    OpenUrlCrossRefPubMed
  168. ↵
    Druker B. J., Sawyers C. L., Kantarjian H., Resta D. J., Reese S. F., Ford J. M., Capdeville R., Talpaz M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med., 344: 1038-1042, 2001.
    OpenUrlCrossRefPubMed
  169. ↵
    Kantarjian H., Sawyers C., Hochhaus A., Guilhot F., Schiffer C., Gambacorti-Passerini C., Niederwieser D., Resta D., Capdeville R., Zoellner U., Talpaz M., Druker B. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med., 346: 645-652, 2002.
    OpenUrlCrossRefPubMed
  170. ↵
    Talpaz M., Silver R. T., Druker B. J., Goldman J. M., Gambacorti-Passerini C., Guilhot F., Schiffer C. A., Fischer T., Deininger M. W., Lennard A. L., Hochhaus A., Ottmann O. G., Gratwohl A., Baccarani M., Stone R., Tura S., Mahon F. X., Fernandes-Reese S., Gathmann I., Capdeville R., Kantarjian H. M., Sawyers C. L. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood, 99: 1928-1937, 2002.
    OpenUrlAbstract/FREE Full Text
  171. ↵
    Dierov J., Xu Q., Dierova R., Carroll M. TEL/platelet-derived growth factor receptor β activates phosphatidylinositol 3 (PI3) kinase and requires PI3 kinase to regulate the cell cycle. Blood, 99: 1758-1765, 2002.
    OpenUrlAbstract/FREE Full Text
  172. ↵
    Golub T. R., Barker G. F., Lovett M., Gilliland D. G. Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell, 77: 307-316, 1994.
    OpenUrlCrossRefPubMed
  173. ↵
    Magnusson M. K., Meade K. E., Brown K. E., Arthur D. C., Krueger L. A., Barrett A. J., Dunbar C. E. Rabaptin-5 is a novel fusion partner to platelet-derived growth factor β receptor in chronic myelomonocytic leukemia. Blood, 98: 2518-2525, 2001.
    OpenUrlAbstract/FREE Full Text
  174. ↵
    Magnusson M. K., Meade K. E., Nakamura R., Barrett J., Dunbar C. E. Activity of STI571 in chronic myelomonocytic leukemia with a platelet- derived growth factor β receptor fusion oncogene. Blood, 100: 1088-1091, 2002.
    OpenUrlAbstract/FREE Full Text
  175. ↵
    Mason D. Y., Bastard C., Rimokh R., Dastugue N., Huret J. L., Kristoffersson U., Magaud J. P., Nezelof C., Tilly H., Vannier J. P., et al CD30-positive large cell lymphomas (’Ki-1 lymphoma’) are associated with a chromosomal translocation involving 5q35, Br. J. Haematol., 74: 161-168, 1990.
    OpenUrl
  176. ↵
    Wellmann A., Otsuki T., Vogelbruch M., Clark H. M., Jaffe E. S., Raffeld M. Analysis of the t(2;5)(p23;q35) translocation by reverse transcription- polymerase chain reaction in CD30+ anaplastic large-cell lymphomas, in other non-Hodgkin’s lymphomas of T-cell phenotype, and in Hodgkin’s disease. Blood, 86: 2321-2328, 1995.
    OpenUrlAbstract/FREE Full Text
  177. ↵
    Bischof D., Pulford K., Mason D. Y., Morris S. W. Role of the nucleophosmin (NPM) portion of the non-Hodgkin’s lymphoma- associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Mol. Cell. Biol., 17: 2312-3325, 1997.
    OpenUrlAbstract/FREE Full Text
  178. ↵
    Fujimoto J., Shiota M., Iwahara T., Seki N., Satoh H., Mori S., Yamamoto T. Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). Proc. Natl. Acad. Sci. USA, 93: 4181-4186, 1996.
    OpenUrlAbstract/FREE Full Text
  179. ↵
    Bai R. Y., Dieter P., Peschel C., Morris S. W., Duyster J. Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-γ to mediate its mitogenicity. Mol. Cell. Biol., 18: 6951-6961, 1998.
    OpenUrlAbstract/FREE Full Text
  180. ↵
    Bai R. Y., Ouyang T., Miething C., Morris S. W., Peschel C., Duyster J. Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood, 96: 4319-4327, 2000.
    OpenUrlAbstract/FREE Full Text
  181. ↵
    Nieborowska-Skorska M., Slupianek A., Xue L., Zhang Q., Raghunath P. N., Hoser G., Wasik M. A., Morris S. W., Skorski T. Role of signal transducer and activator of transcription 5 in nucleophosmin/anaplastic lymphoma kinase-mediated malignant transformation of lymphoid cells. Cancer Res., 61: 6517-6523, 2001.
    OpenUrlAbstract/FREE Full Text
  182. ↵
    Slupianek A., Nieborowska-Skorska M., Hoser G., Morrione A., Majewski M., Xue L., Morris S. W., Wasik M. A., Skorski T. Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. Cancer Res., 61: 2194-2199, 2001.
    OpenUrlAbstract/FREE Full Text
  183. ↵
    Stein H., Foss H. D., Durkop H., Marafioti T., Delsol G., Pulford K., Pileri S., Falini B. CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood, 96: 3681-3695, 2000.
    OpenUrlAbstract/FREE Full Text
  184. ↵
    Sachs L. The control of hematopoiesis and leukemia: from basic biology to the clinic. Proc. Natl. Acad. Sci. USA, 93: 4742-4749, 1996.
    OpenUrlAbstract/FREE Full Text
  185. ↵
    Savino R., Ciapponi L., Lahm A., Demartis A., Cabibbo A., Toniatti C., Delmastro P., Altamura S., Ciliberto G. Rational design of a receptor super-antagonist of human interleukin-6. EMBO J., 13: 5863-5870, 1994.
    OpenUrlPubMed
  186. ↵
    Klein B., Wijdenes J., Zhang X. G., Jourdan M., Boiron J. M., Brochier J., Liautard J., Merlin M., Clement C., Morel-Fournier B., et al Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood, 78: 1198-1204, 1991.
    OpenUrlAbstract/FREE Full Text
  187. ↵
    Tse K. F., Novelli E., Civin C. I., Bohmer F. D., Small D. Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor. Leukemia (Baltimore), 15: 1001-1010, 2001.
    OpenUrlCrossRefPubMed
  188. ↵
    Kottaridis P. D., Gale R. E., Frew M. E., Harrison G., Langabeer S. E., Belton A. A., Walker H., Wheatley K., Bowen D. T., Burnett A. K., Goldstone A. H., Linch D. C. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood, 98: 1752-1759, 2001.
    OpenUrlAbstract/FREE Full Text
  189. ↵
    Abu-Duhier F. M., Goodeve A. C., Wilson G. A., Gari M. A., Peake I. R., Rees D. C., Vandenberghe E. A., Winship P. R., Reilly J. T. FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br. J. Haematol., 111: 190-195, 2000.
    OpenUrlCrossRefPubMed
  190. ↵
    Meydan N., Grunberger T., Dadi H., Shahar M., Arpaia E., Lapidot Z., Leeder J. S., Freedman M., Cohen A., Gazit A., Levitzki A., Roifman C. M. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature (Lond.), 379: 645-648, 1996.
    OpenUrlCrossRefPubMed
  191. ↵
    Eriksen K. W., Kaltoft K., Mikkelsen G., Nielsen M., Zhang Q., Geisler C., Nissen M. H., Ropke C., Wasik M. A., Odum N. Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells. Leukemia (Baltimore), 15: 787-793, 2001.
    OpenUrlCrossRefPubMed
  192. ↵
    De Vos J., Jourdan M., Tarte K., Jasmin C., Klein B. JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. Br. J. Haematol., 109: 823-828, 2000.
    OpenUrlCrossRefPubMed
  193. ↵
    Levitt M. L., Koty P. P. Tyrosine kinase inhibitors in preclinical development. Investig. New Drugs, 17: 213-226, 1999.
    OpenUrlCrossRefPubMed
  194. ↵
    Klohs W. D., Fry D. W., Kraker A. J. Inhibitors of tyrosine kinase. Curr. Opin. Oncol., 9: 562-568, 1997.
    OpenUrlCrossRefPubMed
  195. ↵
    Marra F., Choudhury G. G., Abboud H. E. Interferon-γ-mediated activation of STAT1α regulates growth factor-induced mitogenesis. J. Clin. Investig., 98: 1218-1230, 1996.
    OpenUrlCrossRefPubMed
  196. ↵
    Turkson J., Bowman T., Garcia R., Caldenhoven E., De Groot R. P., Jove R. Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol. Cell. Biol., 18: 2545-2552, 1998.
    OpenUrlAbstract/FREE Full Text
  197. ↵
    Sillaber C., Gesbert F., Frank D. A., Sattler M., Griffin J. D. STAT5 activation contributes to growth and viability in Bcr/Abl-transformed cells. Blood, 95: 2118-2125, 2000.
    OpenUrlAbstract/FREE Full Text
  198. ↵
    Frank D. A., Mahajan S., Ritz J. Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat. Med., 5: 444-447, 1999.
    OpenUrlCrossRefPubMed
  199. ↵
    Minucci S., Nervi C., Lo Coco F., Pelicci P. G. Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?. Oncogene, 20: 3110-3115, 2001.
    OpenUrlCrossRefPubMed
  200. ↵
    Amann J. M., Nip J., Strom D. K., Lutterbach B., Harada H., Lenny N., Downing J. R., Meyers S., Hiebert S. W. ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain. Mol. Cell. Biol., 21: 6470-6483, 2001.
    OpenUrlAbstract/FREE Full Text
  201. ↵
    Guidez F., Zelent A. Role of nuclear receptor corepressors in leukemogenesis. Curr. Top. Microbiol. Immunol., 254: 165-185, 2001.
    OpenUrlPubMed
  202. ↵
    Chakrabarti S. R., Sood R., Nandi S., Nucifora G. Posttranslational modification of TEL and TEL/AML1 by SUMO-1 and cell-cycle-dependent assembly into nuclear bodies. Proc. Natl. Acad. Sci. USA, 97: 13281-13285, 2000.
    OpenUrlAbstract/FREE Full Text
  203. ↵
    Wang J., Saunthararajah Y., Redner R. L., Liu J. M. Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res., 59: 2766-2769, 1999.
    OpenUrlAbstract/FREE Full Text
  204. ↵
    Silverman L. R., Demakos E. P., Peterson B. L., Kornblith A. B., Holland J. C., Odchimar-Reissig R., Stone R. M., Nelson D., Powell B. L., DeCastro C. M., Ellerton J., Larson R. A., Schiffer C. A., Holland J. F. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol., 20: 2429-2440, 2002.
    OpenUrlAbstract/FREE Full Text
  205. ↵
    Dyck J. A., Maul G. G., Miller W. H., Jr., Chen J. D., Kakizuka A., Evans R. M. A novel macromolecular structure is a target of the promyelocyte- retinoic acid receptor oncoprotein. Cell, 76: 333-343, 1994.
    OpenUrlCrossRefPubMed
  206. ↵
    Weis K., Rambaud S., Lavau C., Jansen J., Carvalho T., Carmo-Fonseca M., Lamond A., Dejean A. Retinoic acid regulates aberrant nuclear localization of PML-RAR α in acute promyelocytic leukemia cells. Cell, 76: 345-356, 1994.
    OpenUrlCrossRefPubMed
  207. ↵
    Lin R. J., Nagy L., Inoue S., Shao W., Miller W. H., Jr., Evans R. M. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature (Lond.), 391: 811-814, 1998.
    OpenUrlCrossRefPubMed
  208. ↵
    Guidez F., Ivins S., Zhu J., Soderstrom M., Waxman S., Zelent A. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARα underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood, 91: 2634-2642, 1998.
    OpenUrlAbstract/FREE Full Text
  209. ↵
    Miller W. H., Jr., Waxman S. Differentiation induction as a treatment for hematologic malignancies. Oncogene, 21: 3496-3506, 2002.
    OpenUrlCrossRefPubMed
  210. ↵
    Jansen J. H., de Ridder M. C., Geertsma W. M., Erpelinck C. A., van Lom K., Smit E. M., Slater R., vd Reijden B. A., de Greef G. E., Sonneveld P., Lowenberg B. Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor. Blood, 94: 39-45, 1999.
    OpenUrlAbstract/FREE Full Text
  211. ↵
    Gianni M., Terao M., Fortino I., LiCalzi M., Viggiano V., Barbui T., Rambaldi A., Garattini E. Stat1 is induced and activated by all-trans retinoic acid in acute promyelocytic leukemia cells. Blood, 89: 1001-1012, 1997.
    OpenUrlAbstract/FREE Full Text
  212. ↵
    Kolla V., Weihua X., Kalvakolanu D. V. Modulation of interferon action by retinoids. Induction of murine STAT1 gene expression by retinoic acid(Published erratum appears in J. Biol. Chem., 272: 16068, 1997). J. Biol. Chem., 272: 9742-9748, 1997.
    OpenUrlAbstract/FREE Full Text
  213. ↵
    Matikainen S., Ronni T., Lehtonen A., Sareneva T., Melen K., Nordling S., Levy D. E., Julkunen I. Retinoic acid induces signal transducer and activator of transcription (STAT) 1. STAT2, and p48 expression in myeloid leukemia cells and enhances their responsiveness to interferons. Cell Growth Differ., 8: 687-698, 1997.
    OpenUrlAbstract
  214. ↵
    Miller W. H., Jr., Schipper H. M., Lee J. S., Singer J., Waxman S. Mechanisms of action of arsenic trioxide. Cancer Res., 62: 3893-3903, 2002.
    OpenUrlAbstract/FREE Full Text
  215. ↵
    Chen G. Q., Zhu J., Shi X. G., Ni J. H., Zhong H. J., Si G. Y., Jin X. L., Tang W., Li X. S., Xong S. M., Shen Z. X., Sun G. L., Ma J., Zhang P., Zhang T. D., Gazin C., Naoe T., Chen S. J., Wang Z. Y., Chen Z. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR α/PML proteins. Blood, 88: 1052-1061, 1996.
    OpenUrlAbstract/FREE Full Text
  216. ↵
    Wang Z. G., Rivi R., Delva L., Konig A., Scheinberg D. A., Gambacorti-Passerini C., Gabrilove J. L., Warrell R. P., Jr., Pandolfi P. P. Arsenic trioxide and melarsoprol induce programmed cell death in myeloid leukemia cell lines and function in a PML and PML-RARα independent manner. Blood, 92: 1497-1504, 1998.
    OpenUrlAbstract/FREE Full Text
  217. ↵
    Shao W., Fanelli M., Ferrara F. F., Riccioni R., Rosenauer A., Davison K., Lamph W. W., Waxman S., Pelicci P. G., Lo Coco F., Avvisati G., Testa U., Peschle C., Gambacorti-Passerini C., Nervi C., Miller W. H., Jr. Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR α protein in acute promyelocytic leukemia cells. J. Natl. Cancer Inst., 90: 124-133, 1998.
    OpenUrlFREE Full Text
  218. ↵
    Zhu J., Koken M. H., Quignon F., Chelbi-Alix M. K., Degos L., Wang Z. Y., Chen Z., de The H. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA, 94: 3978-3983, 1997.
    OpenUrlAbstract/FREE Full Text
  219. ↵
    Coiffier B., Lepage E., Briere J., Herbrecht R., Tilly H., Bouabdallah R., Morel P., Van Den Neste E., Salles G., Gaulard P., Reyes F., Lederlin P., Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med., 346: 235-242, 2002.
    OpenUrlCrossRefPubMed
  220. ↵
    Rai K. R. Future strategies toward the cure of indolent B-cell malignancies. New biologic therapies. Semin. Hematol., 36: 12-17, 1999.
    OpenUrlPubMed
  221. ↵
    Keating M. J. Chronic lymphocytic leukemia. Semin. Oncol., 26: 107-114, 1999.
    OpenUrlPubMed
  222. ↵
    Shan D., Ledbetter J. A., Press O. W. Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood, 91: 1644-1652, 1998.
    OpenUrlAbstract/FREE Full Text
  223. ↵
    Byrd J. C., Kitada S., Flinn I. W., Aron J. L., Pearson M., Lucas D., Reed J. C. The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction. Blood, 99: 1038-1043, 2002.
    OpenUrlAbstract/FREE Full Text
  224. ↵
    Reed J. C., Kitada S., Kim Y., Byrd J. Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers. Semin. Oncol., 29: 10-24, 2002.
    OpenUrl
  225. ↵
    Adjei A. A. Blocking oncogenic Ras signaling for cancer therapy. J. Natl. Cancer Inst., 93: 1062-1074, 2001.
    OpenUrlAbstract/FREE Full Text
  226. ↵
    Kohl N. E., Mosser S. D., deSolms S. J., Giuliani E. A., Pompliano D. L., Graham S. L., Smith R. L., Scolnick E. M., Oliff A., Gibbs J. B. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science (Wash. DC), 260: 1934-1937, 1993.
    OpenUrlAbstract/FREE Full Text
  227. ↵
    James G. L., Goldstein J. L., Brown M. S., Rawson T. E., Somers T. C., McDowell R. S., Crowley C. W., Lucas B. K., Levinson A. D., Marsters J. C., Jr. Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science (Wash. DC), 260: 1937-1942, 1993.
    OpenUrlAbstract/FREE Full Text
  228. ↵
    Gibbs J. B. Ras C-terminal processing enzymes-new drug targets?. Cell, 65: 1-4, 1991.
    OpenUrlCrossRefPubMed
  229. ↵
    Karp J. E., Lancet J. E., Kaufmann S. H., End D. W., Wright J. J., Bol K., Horak I., Tidwell M. L., Liesveld J., Kottke T. J., Ange D., Buddharaju L., Gojo I., Highsmith W. E., Belly R. T., Hohl R. J., Rybak M. E., Thibault A., Rosenblatt J. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood, 97: 3361-3369, 2001.
    OpenUrlAbstract/FREE Full Text
  230. ↵
    Karp J. E. Farnesyl protein transferase inhibitors as targeted therapies for hematologic malignancies. Semin. Hematol., 38: 16-23, 2001.
    OpenUrlCrossRefPubMed
  231. ↵
    Adjei A. A., Erlichman C., Davis J. N., Cutler D. L., Sloan J. A., Marks R. S., Hanson L. J., Svingen P. A., Atherton P., Bishop W. R., Kirschmeier P., Kaufmann S. H. A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res., 60: 1871-1877, 2000.
    OpenUrlAbstract/FREE Full Text
  232. ↵
    Kurzrock R., Sebti S. M., Kantarjian H. M., Wright J., Cortes J. E., Thomas D. A., Wilson E., Beran M., Koller C. A., O’Brien S., Freireich E. J., Talpaz M. Phase I Study of a Farnesyl Transferase Inhibitor. R115777, in Patients with Myelodysplastic Syndrome. Blood, 98: 623a 2001.
    OpenUrl
  233. ↵
    Blagosklonny M. V., Fojo T., Bhalla K. N., Kim J. S., Trepel J. B., Figg W. D., Rivera Y., Neckers L. M. The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl- expressing leukemia cells to cytotoxic chemotherapy. Leukemia (Baltimore), 15: 1537-1543, 2001.
    OpenUrlCrossRefPubMed
  234. ↵
    Soga S., Neckers L. M., Schulte T. W., Shiotsu Y., Akasaka K., Narumi H., Agatsuma T., Ikuina Y., Murakata C., Tamaoki T., Akinaga S. KF25706, a novel oxime derivative of radicicol, exhibits in vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules. Cancer Res., 59: 2931-2938, 1999.
    OpenUrlAbstract/FREE Full Text
  235. ↵
    Shiotsu Y., Neckers L. M., Wortman I., An W. G., Schulte T. W., Soga S., Murakata C., Tamaoki T., Akinaga S. Novel oxime derivatives of radicicol induce erythroid differentiation associated with preferential G(1) phase accumulation against chronic myelogenous leukemia cells through destabilization of Bcr-Abl with Hsp90 complex. Blood, 96: 2284-2291, 2000.
    OpenUrlAbstract/FREE Full Text
  236. ↵
    Propper D. J., McDonald A. C., Man A., Thavasu P., Balkwill F., Braybrooke J. P., Caponigro F., Graf P., Dutreix C., Blackie R., Kaye S. B., Ganesan T. S., Talbot D. C., Harris A. L., Twelves C. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J. Clin. Oncol., 19: 1485-1492, 2001.
    OpenUrlAbstract/FREE Full Text
  237. ↵
    Okuda K., Matulonis U., Salgia R., Kanakura Y., Druker B., Griffin J. D. Factor independence of human myeloid leukemia cell lines is associated with increased phosphorylation of the proto-oncogene Raf-1. Exp. Hematol., 22: 1111-1117, 1994.
    OpenUrlPubMed
  238. ↵
    Kang C. D., Yoo S. D., Hwang B. W., Kim K. W., Kim D. W., Kim C. M., Kim S. H., Chung B. S. The inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemic K562 cells. Leuk. Res., 24: 527-534, 2000.
    OpenUrlCrossRefPubMed
  239. ↵
    Kim S. C., Hahn J. S., Min Y. H., Yoo N. C., Ko Y. W., Lee W. J. Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK, hyperexpression of extracellular signal-regulated kinase, and downregulation of a phosphatase. PAC1. Blood, 93: 3893-3899, 1999.
    OpenUrlAbstract/FREE Full Text
  240. ↵
    Morgan M. A., Dolp O., Reuter C. W. Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Blood, 97: 1823-1834, 2001.
    OpenUrlAbstract/FREE Full Text
  241. ↵
    Alessi D. R., Cuenda A., Cohen P., Dudley D. T., Saltiel A. R. PD 098059 is a specific inhibitor of the activation of mitogen- activated protein kinase kinase in vitro and in vivo. J. Biol. Chem., 270: 27489-27494, 1995.
    OpenUrlAbstract/FREE Full Text
  242. ↵
    Dudley D. T., Pang L., Decker S. J., Bridges A. J., Saltiel A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl. Acad. Sci. USA, 92: 7686-7689, 1995.
    OpenUrlAbstract/FREE Full Text
  243. ↵
    Favata M. F., Horiuchi K. Y., Manos E. J., Daulerio A. J., Stradley D. A., Feeser W. S., Van Dyk D. E., Pitts W. J., Earl R. A., Hobbs F., Copeland R. A., Magolda R. L., Scherle P. A., Trzaskos J. M. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem., 273: 18623-18632, 1998.
    OpenUrlAbstract/FREE Full Text
  244. ↵
    Sebolt-Leopold J. S. Development of anticancer drugs targeting the MAP kinase pathway. Oncogene, 19: 6594-6599, 2000.
    OpenUrlCrossRefPubMed
  245. ↵
    Powis G., Bonjouklian R., Berggren M. M., Gallegos A., Abraham R., Ashendel C., Zalkow L., Matter W. F., Dodge J., Grindey G., et al Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3- kinase. Cancer Res., 54: 2419-2423, 1994.
    OpenUrlAbstract/FREE Full Text
  246. ↵
    Vlahos C. J., Matter W. F., Hui K. Y., Brown R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4- morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem., 269: 5241-5248, 1994.
    OpenUrlAbstract/FREE Full Text
  247. ↵
    Roth W., Reed J. C. Apoptosis and cancer: when BAX is TRAILing away. Nat. Med., 8: 216-218, 2002.
    OpenUrlCrossRefPubMed
  248. ↵
    Buolamwini J. K. Novel anticancer drug discovery. Curr. Opin. Chem. Biol., 3: 500-509, 1999.
    OpenUrlCrossRefPubMed
  249. ↵
    Martin S. J. Destabilizing influences in apoptosis: sowing the seeds of IAP destruction. Cell, 109: 793-796, 2002.
    OpenUrlCrossRefPubMed
  250. ↵
    Stennicke H. R., Ryan C. A., Salvesen G. S. Reprieval from execution: the molecular basis of caspase inhibition. Trends Biochem. Sci., 27: 94-101, 2002.
    OpenUrlCrossRefPubMed
  251. ↵
    LaCasse E. C., Baird S., Korneluk R. G., MacKenzie A. E. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene, 17: 3247-3259, 1998.
    OpenUrlCrossRefPubMed
  252. ↵
    Holcik M., Gibson H., Korneluk R. G. XIAP: apoptotic brake and promising therapeutic target. Apoptosis, 6: 253-261, 2001.
    OpenUrlCrossRefPubMed
  253. ↵
    Tamm I., Kornblau S. M., Segall H., Krajewski S., Welsh K., Kitada S., Scudiero D. A., Tudor G., Qui Y. H., Monks A., Andreeff M., Reed J. C. Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin. Cancer Res., 6: 1796-1803, 2000.
    OpenUrlAbstract/FREE Full Text
  254. ↵
    Holcik M., Yeh C., Korneluk R. G., Chow T. Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. Oncogene, 19: 4174-4177, 2000.
    OpenUrlCrossRefPubMed
  255. ↵
    Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell, 79: 13-21, 1994.
    OpenUrlCrossRefPubMed
  256. ↵
    Almond J. B., Cohen G. M. The proteasome: a novel target for cancer chemotherapy. Leukemia (Baltimore), 16: 433-443, 2002.
    OpenUrlCrossRefPubMed
  257. ↵
    King R. W., Deshaies R. J., Peters J. M., Kirschner M. W. How proteolysis drives the cell cycle. Science (Wash. DC), 274: 1652-1659, 1996.
    OpenUrlAbstract/FREE Full Text
  258. ↵
    Karin M., Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[κ]B activity. Annu. Rev. Immunol., 18: 621-663, 2000.
    OpenUrlCrossRefPubMed
  259. ↵
    Chang Y. C., Lee Y. S., Tejima T., Tanaka K., Omura S., Heintz N. H., Mitsui Y., Magae J. mdm2 and bax, downstream mediators of the p53 response, are degraded by the ubiquitin-proteasome pathway. Cell Growth Differ., 9: 79-84, 1998.
    OpenUrlAbstract
  260. ↵
    Breitschopf K., Zeiher A. M., Dimmeler S. Ubiquitin-mediated degradation of the proapoptotic active form of bid. A functional consequence on apoptosis induction. J. Biol. Chem., 275: 21648-21652, 2000.
    OpenUrlAbstract/FREE Full Text
  261. ↵
    Li B., Dou Q. P. Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. Proc. Natl. Acad. Sci. USA, 97: 3850-3855, 2000.
    OpenUrlAbstract/FREE Full Text
  262. ↵
    Marshansky V., Wang X., Bertrand R., Luo H., Duguid W., Chinnadurai G., Kanaan N., Vu M. D., Wu J. Proteasomes modulate balance among proapoptotic and antiapoptotic Bcl-2 family members and compromise functioning of the electron transport chain in leukemic cells. J. Immunol., 166: 3130-3142, 2001.
    OpenUrlAbstract/FREE Full Text
  263. ↵
    Gardner R. C., Assinder S. J., Christie G., Mason G. G., Markwell R., Wadsworth H., McLaughlin M., King R., Chabot-Fletcher M. C., Breton J. J., Allsop D., Rivett A. J. Characterization of peptidyl boronic acid inhibitors of mammalian 20 S and 26 S proteasomes and their inhibition of proteasomes in cultured cells. Biochem. J., 346 Pt 2: 447-454, 2000.
  264. ↵
    Almond J. B., Snowden R. T., Hunter A., Dinsdale D., Cain K., Cohen G. M. Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex. Leukemia (Baltimore), 15: 1388-1397, 2001.
    OpenUrlCrossRefPubMed
  265. ↵
    Masdehors P., Omura S., Merle-Beral H., Mentz F., Cosset J. M., Dumont J., Magdelenat H., Delic J. Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Br. J. Haematol., 105: 752-757, 1999.
    OpenUrlCrossRefPubMed
  266. ↵
    Masdehors P., Merle-Beral H., Maloum K., Omura S., Magdelenat H., Delic J. Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes. Blood, 96: 269-274, 2000.
    OpenUrlAbstract/FREE Full Text
  267. ↵
    Chandra J., Niemer I., Gilbreath J., Kliche K. O., Andreeff M., Freireich E. J., Keating M., McConkey D. J. Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. Blood, 92: 4220-4229, 1998.
    OpenUrlAbstract/FREE Full Text
  268. ↵
    Adams J., Palombella V. J., Sausville E. A., Johnson J., Destree A., Lazarus D. D., Maas J., Pien C. S., Prakash S., Elliott P. J. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res., 59: 2615-2622, 1999.
    OpenUrlAbstract/FREE Full Text
  269. ↵
    Hideshima T., Richardson P., Chauhan D., Palombella V. J., Elliott P. J., Adams J., Anderson K. C. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res., 61: 3071-3076, 2001.
    OpenUrlAbstract/FREE Full Text
  270. ↵
    Hideshima T., Chauhan D., Richardson P., Mitsiades C., Mitsiades N., Hayashi T., Munshi N., Dang L., Castro A., Palombella V., Adams J., Anderson K. C. NF-κ B as a therapeutic target in multiple myeloma. J. Biol. Chem., 277: 16639-16647, 2002.
    OpenUrlAbstract/FREE Full Text
  271. ↵
    Mitsiades N., Mitsiades C. S., Poulaki V., Chauhan D., Richardson P. G., Hideshima T., Munshi N., Treon S. P., Anderson K. C. Biologic sequelae of nuclear factor-κB blockade in multiple myeloma: therapeutic applications. Blood, 99: 4079-4086, 2002.
    OpenUrlAbstract/FREE Full Text
  272. ↵
    Sherr C. J. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res., 60: 3689-3695, 2000.
    OpenUrlAbstract/FREE Full Text
  273. ↵
    Sellers W. R., Rodgers J. W., Kaelin W. G., Jr. A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites, Proc. Natl. Acad. Sci. USA, 92: 11544-11548, 1995.
    OpenUrlAbstract/FREE Full Text
  274. ↵
    Magnaghi-Jaulin L., Groisman R., Naguibneva I., Robin P., Lorain S., Le Villain J. P., Troalen F., Trouche D., Harel-Bellan A. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature (Lond.), 391: 601-605, 1998.
    OpenUrlCrossRefPubMed
  275. ↵
    Krug U., Ganser A., Koeffler H. P. Tumor suppressor genes in normal and malignant hematopoiesis. Oncogene, 21: 3475-3495, 2002.
    OpenUrlCrossRefPubMed
  276. ↵
    Sauerbrey A., Stammler G., Zintl F., Volm M. Expression of the retinoblastoma tumor suppressor gene (RB-1) in acute leukemia. Leuk. Lymphoma, 28: 275-283, 1998.
    OpenUrlPubMed
  277. ↵
    Drexler H. G. Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia (Baltimore), 12: 845-859, 1998.
    OpenUrlCrossRefPubMed
  278. ↵
    Chim C. S., Liang R., Tam C. Y., Kwong Y. L. Methylation of p15 and p16 genes in acute promyelocytic leukemia: potential diagnostic and prognostic significance. J. Clin. Oncol., 19: 2033-2040, 2001.
    OpenUrlAbstract/FREE Full Text
  279. ↵
    Senderowicz A. M. Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies. Leukemia (Baltimore), 15: 1-9, 2001.
    OpenUrlCrossRefPubMed
  280. ↵
    Shapiro G. I., Harper J. W. Anticancer drug targets: cell cycle and checkpoint control. J. Clin. Investig., 104: 1645-1653, 1999.
    OpenUrlCrossRefPubMed
  281. ↵
    Sausville E. A., Arbuck S. G., Messmann R., Headlee D., Bauer K. S., Lush R. M., Murgo A., Figg W. D., Lahusen T., Jaken S., Jing X., Roberge M., Fuse E., Kuwabara T., Senderowicz A. M. Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J. Clin. Oncol., 19: 2319-2333, 2001.
    OpenUrlAbstract/FREE Full Text
Back to top
Clinical Cancer Research: 9 (2)
February 2003
Volume 9, Issue 2

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Email Article
Citation Tools
Modulation of Cellular Signaling Pathways
Farhad Ravandi, Moshe Talpaz and Zeev Estrov
Clin Cancer Res February 1 2003 (9) (2) 535-550;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

Advertisement