Clinical Cancer Research CR Balducci AACR Membership
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Clinical Cancer Research 13, 6964, December 1, 2007. doi: 10.1158/1078-0432.CCR-07-1474
© 2007 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mansour, M. R.
Right arrow Articles by Linch, D. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mansour, M. R.
Right arrow Articles by Linch, D. C.

Human Cancer Biology

Notch-1 Mutations Are Secondary Events in Some Patients with T-Cell Acute Lymphoblastic Leukemia

Marc R. Mansour1, Veronique Duke2, Letizia Foroni2, Bella Patel2, Christopher G. Allen1, Phil J. Ancliff3, Rosemary E. Gale1 and David C. Linch1

Authors' Affiliations: 1 Department of Haematology, University College London; 2 Department of Haematology, Royal Free Hospital; and 3 Great Ormond Street Hospital, London, United Kingdom

Requests for reprints: Marc R. Mansour, Department of Haematology, University College London, 98 Chenies Mews, London WC1E 6HX, United Kingdom. E-mail: m.mansour{at}ucl.ac.uk.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Activating Notch-1 mutations are frequent in T-cell acute lymphoblastic leukemia (T-ALL), occurring in >50% of patients. In murine models of T-ALL, Notch-1 activation can both directly initiate leukemia and cooperate secondarily to other primary events. Whether acquisition of Notch-1 mutations is an early initiating event or a secondary event in the pathogenesis of human T-ALL is unclear.

Experimental Design: We used denaturing high-performance liquid chromatography, sequencing, and fragment analysis to analyze Notch-1 mutational status and mutant level in 62 patients at presentation as well as 16 matched presentation-relapse samples.

Results: We detected Notch-1 mutations in 47 patients (76%). Seven of these were low-level mutations (quantified at ≤10%), despite high blast counts, suggesting that they were acquired as a secondary event in a subclone. Of 16 matched presentation-relapse samples studied, 7 were wild-type at both presentation and relapse. Five of nine mutant-positive patients at presentation relapsed with the same mutation(s) at the same high level. Four patients had evidence of a change in mutant at relapse. One lost a PEST mutation and became wild-type. Two others lost mutations at relapse but acquired different mutations, despite unchanged T-cell receptor rearrangements, suggesting that the latter event predated the acquisition of the Notch-1 mutation. One relapsed with a secondary T-cell leukemia and different Notch mutation.

Conclusions: These results suggest that Notch-1 mutations can sometimes be acquired as secondary events in leukemogenesis and must be used cautiously as solitary minimal residual disease markers.

Notch-1 is thought to play an important role in normal hematopoiesis, where it has been implicated in maintenance of the hematopoietic stem cell niche (1), hematopoietic stem cell self-renewal (2, 3), and determination of lymphoid progenitor cell fate (4). It is a transmembrane receptor and ligand binding to the extracellular domain causes a conformational change in the heterodimerization (HD) domain, exposing sites to cleavage first by a disintegrin and metalloproteinase and then by {gamma}-secretase at the transmembrane domain. This liberates intracellular Notch-1 (ICN) to translocate to the nucleus and induce downstream signaling events (5–7).

The first evidence implicating aberrant Notch signaling in leukemogenesis came from identification of the rare t(7;9) translocation in three pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL), which juxtaposed the T-cell receptor (TCR) β promoter with ICN and led to constitutive Notch-1 activation (8). Subsequently, activating Notch-1 mutations have been found as a frequent occurrence in both pediatric and adult T-ALL, being detected in >50% of patients at disease presentation (9–11). Mutations tend to cluster in two hotspots: the HD, where they are associated with ligand-independent cleavage of ICN (12), and the PEST domain, where they lead to a COOH-terminally truncated ICN. The latter results in loss of the negative regulatory domain, escape from FBXW7-mediated degradation and prolongation of the half-life of ICN (9, 13, 14). Approximately 20% of patients have mutations in both domains, usually occurring in cis, which results in synergistic Notch activation (9). Increased ICN levels have recently been shown to activate important oncogenes, including c-Myc and mammalian target of rapamycin (15–17).

The role of Notch as a primary event in leukemogenesis has been recapitulated in murine models, where animals transplanted with cells transduced with either ICN or the Notch ligand Delta-like 4 developed a lethal T-cell leukemia (18–20). Interestingly, Notch-1 mutations have also been found in the majority of mice with TAL-1–induced T-ALL as well as in mice deficient in various combinations of TP53, HAXA2, and Rag2 genes, suggesting that Notch-1 mutations can occur as secondary events and play a collaborative role in T-ALL pathogenesis (21, 22).

In human T-ALL while Notch-1 mutations occur in all cytogenetic and molecular subgroups, it is unclear whether they are primary initiating or secondary cooperating events. To address this issue, we have assessed the relative level of Notch-1 mutated alleles in a cohort of human patients at presentation with T-ALL and examined stability of these mutations at disease relapse.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patients and samples. Ethical approval for tissue collection for research was obtained from the Multi-Centre Research Ethics Committee for patients entered into clinical trials or from local research ethics committees as appropriate, and informed consent was obtained according to the Declaration of Helsinki. DNA was extracted from bone marrow samples or aspirate slides from 62 patients at presentation with T-ALL (46 adults and 16 children); results on 24 adults were reported previously (10). Samples were available from 16 patients at first relapse; 3 also had samples at second relapse.

Notch-1 mutational analysis. Notch-1 mutation screening and identification were carried out using heteroduplex analysis and sequencing as previously reported (10). The HD-N, HD-C, transactivation (TAD), and PEST domains were amplified by 35 cycles of the PCR using the primer sequences shown in Table 1 . The proofreading enzyme Optimase (Transgenomic) was used according to the manufacturer's specifications for the TAD and HD-C domain with the inclusion of 1 mol/L betaine due to the high GC content of these fragments. However, products of adequate quality could not be obtained using Optimase for the HD-N and PEST domains, and these fragments were amplified using BioTAQ DNA polymerase (Bioline). PCR products were analyzed by denaturing high-performance liquid chromatography (WAVE DNA Fragment Analysis System, Transgenomic). Abnormal chromatograms were confirmed by repeat analysis and samples were sequenced using the Dye Terminator Cycle Sequencing Quick Start kit and analyzed on the CEQ8000 Genetic Analysis System (Beckman Coulter).


View this table:
[in this window]
[in a new window]

  		Table 1. Notch-1 primer sequences and annealing temperatures

 
For samples where the heteroduplex peaks were much smaller than the homoduplex peaks, the former were purified using the fragment collector facility of the WAVE and sequenced. In samples with insertions or deletions, relative mutant levels were quantified using the methods described above except one primer was fluorescently labeled and only 30 cycles of amplification were done. Products were size separated using fragment analysis on the CEQ8000 Genetic Analysis System. For one sample, a mutant-specific oligonucleotide was designed corresponding to the mutation, and quantification was done using the LightCycler rapid thermal cycler system (Roche Diagnostics Ltd.).

TCR rearrangements. TCR rearrangements were determined at the TCR {gamma} locus using heteroduplex analysis and fluorescently labeled primers as previously reported (23–25). For those patients where no suitable marker was detected at the {gamma} locus, the {delta} locus was analyzed.

Same patient identity. Same patient identity was confirmed in the paired presentation-relapse samples using size analysis at four highly informative polymorphic short tandem repeat loci (VWA, FES, D11S-554, and F13I; ref. 26). PCRs were carried out using BioTAQ DNA polymerase, a fluorescently labeled forward primer, and 30 cycles of amplification with annealing temperatures of 54°C for F131, FES, and VWA and 61°C for D11S-554. Products were sized by fragment analysis.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Notch-1 mutation level. Of the 38 new cases in this cohort of adult and pediatric patients, 30 had one or more Notch-1 mutations, giving an overall incidence of 47 mutant-positive (76%) patients in the total cohort of 62. This is similar to the incidence observed (71%) in our earlier study of 24 adult patients (10). Most of the 60 mutations detected had heteroduplex patterns that were suggestive of the presence of the mutation in the majority of cells, assuming heterozygosity (Fig. 1 ). Allele quantification using size analysis was feasible for 32 of the mutations that were either insertions or deletions. The median mutant level was 40% of total Notch alleles (range, 5-49%; Fig. 2 ). For 22 of the mutations, the mutant level was >30% of total alleles and therefore consistent with the presence of a heterozygous mutation in the majority of cells (≥60%). However, for 10 mutations, the mutant level was <30% and in six of these it was ≤10% (Fig. 2), indicating that ≤20% of cells carried the mutation (Table 2 ). Two of these low-level mutations were in the same patient (#50; Table 2). The remaining 27 mutations were nucleotide substitutions, which were not amenable to quantification. Of these, only one case (#40) had an apparent low-level mutation by visual estimation of the WAVE chromatogram, and all others were high level. The low-level mutants were not due to the presence of normal cells, as in each patient morphologic examination revealed at least 75% leukemic blasts. Furthermore, three of these patients had a high-level mutation in another domain. This suggested that the low-level mutations were acquired in a subclone as a later event. None of the patients with low-level mutations had evidence of ploidy or loss of genomic material of chromosome 9q by G-banding cytogenetics.


Figure 1
View larger version (13K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. WAVE chromatograms of the HD-N according to mutant level. A, WT chromatogram of the HD-N seen as a single peak. B, a high-level heteroduplex pattern of the HD-N (insV1579/1580; quantified at 48% by fragment analysis) of case 54. Similar high-level patterns were seen in the majority of mutant-positive patients. C, a low-level heteroduplex pattern (F1593L;1594InsSP) in the HD-N (case 22; quantified at 6% by fragment analysis).

 

Figure 2
View larger version (10K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Distribution of mutant level for 32 insertions or deletions. Mutation level as quantified by labeled primer and fragment analysis.

 

View this table:
[in this window]
[in a new window]

  		Table 2. Mutant level and features of patients with low-level Notch-1 mutations

 
Paired presentation-relapse samples. To further examine whether the low-level mutations might have been acquired as secondary events, we studied paired presentation-relapse samples from 16 patients. Short tandem repeat analysis of four loci confirmed that all paired samples were from the same individual. Seven cases were wild-type (WT) at both presentation and relapse (Fig. 3A ). Of nine mutant-positive patients at presentation, five relapsed with the same mutation(s) at approximately the same or increased mutant level (#8-11; Table 3 ). In one patient (#10), the same mutation was also present at second relapse. In two patients (#11 and #12), high-level mutations were present in two different domains, both of which recurred at relapse, suggesting they were in the same cell. In these five patients, it is likely that the Notch mutation occurred as an early event. However, in four mutant-positive patients, there were changes at relapse.


Figure 3
View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. WAVE chromatograms and fragment analysis for paired presentation-relapse cases. A, a high-level PEST domain mutation (11-bp insertion leading to frameshift at amino acid 2444) recurred at relapse (case 10). B, a high-level (39% mutant) PEST domain mutation (insertion of stop codon at amino acid 2468) was lost at relapse (case 13). C, case 15 developed a new high-level HD-N mutation (H1592Q;F1593T) at relapse, which was undetectable in the presentation sample by quantitative PCR. D to F, progressive increase of a 39-bp insertion in the HD-C domain (case 14).

 

View this table:
[in this window]
[in a new window]

  		Table 3. Notch-1 mutational status at presentation and relapse in 16 patients with T-ALL

 
At presentation, one patient (#13) had only a PEST domain mutation (insertion of stop codon at amino acid 2468), which was not detected at relapse (Fig. 3B). The same TCR V{gamma}1 clone was identified at both presentation and relapse. Case 15 had a low-level HD-C mutation at presentation (delV1677; 9% mutant) that was undetectable at relapse. However, the patient relapsed with a new high-level HD-N mutation (H1592Q;F1593T; Fig. 3C). To determine whether the HD-N mutation was present at diagnosis but below the level of detection of the WAVE analysis, mutant-specific quantitative PCR was done on the presentation sample. The HD-N mutation could not be detected at a sensitivity of 1 x 10–4. Furthermore, the same TCR V{gamma}1 clone was seen at both presentation and relapse. Another patient (#14) had an 11-bp insertion in the PEST domain at presentation, which was not detected at first or second relapse (22 and 29 months, respectively). However, a 39-bp insertion in the HD-C domain was present at a low level (6%) at diagnosis and progressively increased at each relapse (21% and 33%, respectively; Fig. 3D-F). Of note, at each time point, the patient had the same TCR V{gamma}11 clone; no new clone was detectable. In these three cases, the results indicate that the Notch-1 mutations occurred after the TCR rearrangement.

Case 16 presented at 5 months of age and relapsed 20 months later. Two high-level mutations (H1545P and S2514F), which were detected at presentation, were lost at relapse, but a new high-level (34% mutant) 2-bp deletion in the PEST domain was acquired. TCR analysis at the {gamma} locus showed loss of the original clone and acquisition of a new unrelated clone (V{gamma}4 to V{gamma}2 clone, respectively), with different CDR3 sequence. Therefore, in this patient, the results probably reflect development of a secondary leukemia, similar to cases described previously (25).


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
As increasing numbers of genetic abnormalities are being described in T-ALL (27, 28), it has become feasible to examine the chronology in which these molecular events are acquired. Such information could help to elucidate the mechanisms by which oncogenic pathways interact, further characterize the leukemic stem cell responsible for relapse, and possibly rationalize the molecular pathways that could be targeted for drug development.

In murine models of T-ALL, Notch activation can both directly induce leukemia and collaborate with other initiating genetic events to perpetuate leukemic growth (18–22). Mice transgenic for SCL/LMO1 usually acquire a Notch-1 mutation by the time of overt transformation to T-ALL (22). Oligoclonality predates acquisition of the mutation, but it is not until after the latter event that these thymocytes can form transplantable tumors. Whether Notch-1 mutations are an initiating or secondary collaborating event in human T-ALL is unclear. Our results suggest that both events may occur.

Of the 59 mutations detected in the total cohort of 62 patients, 49 were present at a high level, which was consistent with the presence of a heterozygous mutation in the majority of cells. Furthermore, in five of nine mutant-positive patients in our paired presentation-relapse cohort, the same mutation was present at relapse. In these patients, it is likely that the mutation had occurred early in disease pathogenesis. Two of these patients had mutations in both the HD and PEST domains at presentation and relapse, suggesting they are in the same cell. In vitro studies have shown that double mutations of this nature cause synergistic Notch activation when in cis (9). It is also noteworthy that two patients (#14 and #9) had evidence of increasing mutant level and one (#15) acquired a new high-level mutation at relapse, suggesting that Notch activation may offer a selection advantage to these cells. The two mutations identified in patient 16 deserve particular mention. The H1545P mutation in exon 26 lies upstream of the HD-N in the third Lin12/Notch repeat (LNR-C); this domain has been shown to play an important role in preventing Notch activation in invertebrates and in vitro (29, 30). This mutation was undetectable in the remission sample and thus a true disease-associated mutation rather than constitutional polymorphism and is the first mutation to be described in this domain in T-ALL. Additionally, the S2514F mutation in the PEST domain of this patient involves a highly conserved serine residue, mutation of which prevents cyclin-dependent kinase 8–mediated Notch-1 hyperphosphorylation and leads to stabilization of ICN (31). Whereas most PEST mutations introduce frameshifts or stop codons upstream of S2514, point mutations of this residue have not been reported and provide a potentially novel mechanism of Notch activation.

Results in some of our patients suggested that the Notch-1 mutations occurred not as a primary event but later in the pathogenesis of the disease. Seven were present at a particularly low level. This was not due to large numbers of normal hematopoietic cells, as review of the morphology showed that all cases had blast counts of ≥74%. A low mutant level could occur if the majority of leukemic cells either lost genomic material, including a mutated Notch-1 allele, or gained copies of the WT allele. However, genomic loss of 9q34 has not been described by either genome-wide analysis or fluorescent in situ hybridization in two substantial cohorts of T-ALL patients (32–34). Furthermore, the finding that T-ALL tumors frequently acquire a second synergistically activating Notch-1 mutation suggests that leukemic cells favor increased, rather than decreased, Notch signal strength, making genomic loss of mutated Notch alleles unlikely. Although homozygosity of the Notch-1 mutated allele has been found in some T-ALL lines as a result of loss of heterozygosity (22), the fact that no patient in our cohort had a mutant level of >50% supports the finding of others that this is not a common phenomenon in human T-ALL (32–34). Notch-1 gene duplication has been described in T-ALL, occurring in a small population of cells as a subclonal phenomenon (35), supporting the hypothesis that Notch activation can be a late secondary event. However, the low mutant levels observed in our cases could only be explained by duplication of the WT gene in the majority of cells with the mutant-carrying clone in the minority. Our results therefore suggest that the low-level mutants described here are due to the gain of a mutation in a subclone, which, in the presence of high blast counts, must be a secondary event. These results were supported by the demonstration that three mutations were lost at relapse, whereas the TCR rearrangements remained unchanged. This suggests the Notch-1 mutation was acquired after the TCR rearrangement in these three patients, a situation analogous to the secondarily acquired Notch-1 mutations in murine models of T-ALL.

The acquisition of Notch-1 mutations at different stages of disease may influence the role of Notch in disease pathogenesis. Early development of a mutation may lead to expansion of the T-cell population before acquisition of other pathogenic events, whereas with later development its effect on activation of other oncogenic pathways may be more important (15–17). Irrespective of the underlying mechanisms, however, results of the current study have implications for Notch as a target both for minimal residual disease analysis and for therapy. The high incidence of Notch-1 mutations in both pediatric and adult patients makes it an attractive target for minimal residual disease analysis, although its application would also be challenging due to the complexity of some of the mutations. Nevertheless, the lack of mutation stability at relapse and the evident acquisition after the TCR rearrangement observed in a proportion of our patients means that caution should be exercised in using them as solitary markers for minimal residual disease analysis. In addition, there may be implications for Notch pathway inhibitors that are currently in clinical trials, which, even if effective against constitutively activated mutant-positive cells, may select out remaining WT leukemic cells.


   Footnotes
 
Grant support: Medical Research Council of the United Kingdom (M.R. Mansour, C.G. Allen, R.E. Gale, and D.C. Linch) and Leukaemia Research Fund, United Kingdom (V. Duke, L. Foroni, and B. Patel).

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.

Received 6/15/07; revised 8/ 7/07; accepted 8/15/07.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003;425:841–6.[CrossRef][Medline]
  2. Delaney C, Varnum-Finney B, Aoyama K, Brashem-Stein C, Bernstein ID. Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood 2005;106:2693–9.[Abstract/Free Full Text]
  3. Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006;442:823–6.[CrossRef][Medline]
  4. Wilson A, MacDonald HR, Radtke F. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J Exp Med 2001;194:1003–12.[Abstract/Free Full Text]
  5. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678–89.[CrossRef][Medline]
  6. Brou C, Logeat F, Gupta N, et al. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 2000;5:207–16.[CrossRef][Medline]
  7. Struhl G, Greenwald I. Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 1999;398:522–5.[CrossRef][Medline]
  8. Ellisen LW, Bird J, West DC, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991;66:649–61.[CrossRef][Medline]
  9. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269–71.[Abstract/Free Full Text]
  10. Mansour MR, Linch DC, L Foroni, Goldstone AH, Gale RE. High incidence of Notch-1 mutations in adult patients with T-cell acute lymphoblastic leukemia. Leukemia 2006;20:537–9.[CrossRef][Medline]
  11. Breit S, Stanulla M, Flohr T, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 2006;108:1151–7.[Abstract/Free Full Text]
  12. Malecki MJ, Sanchez-Irizarry C, Mitchell JL, et al. Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol Cell Biol 2006;26:4642–51.[Abstract/Free Full Text]
  13. Gupta-Rossi N, Le Bail O, Gonen H, et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor. J Biol Chem 2001;276:34371–8.[Abstract/Free Full Text]
  14. Wu G, Lyapina S, Das I, et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol Cell Biol 2001;21:7403–15.[Abstract/Free Full Text]
  15. Sharma VM, Calvo JA, Draheim KM, et al. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol 2006;26:8022–31.[Abstract/Free Full Text]
  16. Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ. Notch signals positively regulate activity of the mTOR pathway in T cell acute lymphoblastic leukemia. Blood 2007;110:278–86.[Abstract/Free Full Text]
  17. Weng AP, Millholland JM, Yashiro-Ohtani Y, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006;20:2096–109.[CrossRef][Medline]
  18. Pear WS, Aster JC, Scott ML, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996;183:2283–91.[Abstract/Free Full Text]
  19. van den Brandt J, Kwon SH, McPherson KG, et al. Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats. Eur J Immunol 2006;36:2223–34.[CrossRef][Medline]
  20. Yan XQ, Sarmiento U, Sun Y, et al. A novel Notch ligand, Dll4, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer. Blood 2001;98:3793–9.[Abstract/Free Full Text]
  21. O'Neil J, Calvo J, McKenna K, et al. Activating Notch1 mutations in mouse models of T-ALL. Blood 2006;107:781–5.[Abstract/Free Full Text]
  22. Lin YW, Nichols RA, Letterio JJ, Aplan PD. Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma. Blood 2006;107:2540–3.[Abstract/Free Full Text]
  23. Gameiro P, Mortuza FY, Hoffbrand AV, Foroni L. Minimal residual disease monitoring in adult T-cell acute lymphoblastic leukemia: a molecular based approach using T-cell receptor and gene rearrangements. Haematologica 2002;87:1126–34.[Abstract/Free Full Text]
  24. van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003;17:2257–31.[CrossRef][Medline]
  25. Szczepanski T, van der Velden VHJ, Raff T, et al. Comparative analysis of T-cell receptor gene rearrangements at diagnosis and relapse of T-cell acute lymphoblastic leukemia (T-ALL) shows high stability of clonal markers for monitoring of minimal residual disease and reveals the occurrence of second T-ALL. Leukemia 2003;17:2149–56.[CrossRef][Medline]
  26. Sellathamby S, Balasubramanian P, Sivalingam S, et al. Developing an algorithm of informative markers for evaluation of chimerism after allogeneic bone marrow transplantation. Bone Marrow Transplant 2006;37:751–5.[CrossRef][Medline]
  27. Graux C, Cools J, Michaux L, Vandenberghe P, Hagemeijer A. Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia 2006;20:1496–510.[CrossRef][Medline]
  28. Maser RS, Choudhury B, Campbell PJ, et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 2007;447:966–71.[CrossRef][Medline]
  29. Greenwald I, Seydoux G. Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans. Nature 1990;346:197–9.[CrossRef][Medline]
  30. Sanchez-Irizarry C, Carpenter AC, Weng AP, Pear WS, Aster JC, Blacklow SC. Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol Cell Biol 2004;24:9265–73.[Abstract/Free Full Text]
  31. Fryer CJ, White JB, Jones KA. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 2004;16:509–20.[CrossRef][Medline]
  32. Irving JA, Bloodworth L, Bown NP, et al. Loss of heterozygosity in childhood acute lymphoblastic leukemia detected by genome-wide microarray single nucleotide polymorphism analysis. Cancer Res 2005;65:3053–8.[Abstract/Free Full Text]
  33. Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007;446:758–64.[CrossRef][Medline]
  34. Wang Y, Armstrong SA. Genome-wide SNP analysis in cancer: leukemia shows the way. Cancer Cell 2007;11:308–9.[CrossRef][Medline]
  35. Vlierberghe P, Meijerink1 JPP, Lee C, et al. A new recurrent 9q34 duplication in pediatric T-cell acute lymphoblastic leukemia. Leukemia 2006;20:1245–53.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 BloodHome page
W. R. Gordon, M. Roy, D. Vardar-Ulu, M. Garfinkel, M. R. Mansour, J. C. Aster, and S. C. Blacklow
Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL
Blood, April 30, 2009; 113(18): 4381 - 4390.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
A.-C. Tien, A. Rajan, and H. J. Bellen
A Notch updated
J. Cell Biol., March 9, 2009; 184(5): 621 - 629.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
D. S. Levy, J. A. Kahana, and R. Kumar
AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines
Blood, February 19, 2009; 113(8): 1723 - 1729.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mansour, M. R.
Right arrow Articles by Linch, D. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mansour, M. R.
Right arrow Articles by Linch, D. C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online