Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium
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
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 Sperr, W. R.
Right arrow Articles by Valent, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sperr, W. R.
Right arrow Articles by Valent, P.
Clinical Cancer Research Vol. 11, 6787-6792, October 1, 2005
© 2005 American Association for Cancer Research

Human Cancer Biology

Myelomastocytic Leukemia: Evidence for the Origin of Mast Cells from the Leukemic Clone and Eradication by Allogeneic Stem Cell Transplantation

Wolfgang R. Sperr1, Johannes Drach2, Alexander W. Hauswirth1, Jutta Ackermann2, Margit Mitterbauer3, Gerlinde Mitterbauer4, Manuela Foedinger4, Christa Fonatsch5, Ingrid Simonitsch-Klupp6, Peter Kalhs3 and Peter Valent1

Authors' Affiliations: 1 Department of Internal Medicine I, Division of Hematology and Hemostaseology; 2 Department of Internal Medicine I, Division of Oncology-the Center of Excellence in Clinical and Experimental Oncology (CLEXO); 3 Department of Internal Medicine I, Division of Bone Marrow Transplantation; 4 Clinical Institute of Medical and Chemical Laboratory Diagnostics; 5 Institute of Medical Biology; and 6 Institute for Clinical Pathology, Medical University of Vienna, Austria

Requests for reprints: Wolfgang R. Sperr, Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Phone: 43-1-404-6085; Fax: 43-1-402-6930; E-mail: wolfgang.r.sperr{at}meduniwien.ac.at.


   Abstract
Top
 Abstract
Patient and Methods
 Results
 Discussion
 References
 
Purpose: Myelomastocytic leukemia is a term used for patients with advanced myeloid neoplasms, in whom elevated numbers of immature atypical mast cells are found, but criteria for a primary mast cell disease are not met. The origin of mast cells in these patients is presently unknown.

Patient and Methods: We have analyzed clonality of mast cells in an 18-year-old patient suffering from acute myeloid leukemia with a complex karyotype including a t(8;21) and mastocytic transformation with a huge increase in immature mast cells and elevated serum tryptase level, but no evidence for a primary mast cell disease/mastocytosis.

Results: As assessed by in situ fluorescence hybridization combined with tryptase staining, both the tryptase-negative blast cells and the tryptase-positive mast cells were found to contain the t(8;21)-specific AML1/ETO fusion gene. Myeloablative stem cell transplantation resulted in complete remission with consecutive disappearance of AML1/ETO transcripts, decrease of serum tryptase to normal range, and disappearance of neoplastic mast cells.

Conclusion: These data suggest that mast cells directly derive from the leukemic clone in patients with myelomastocytic leukemia.

Myelomastocytic leukemia is a term used for patients with advanced myeloid neoplasms, in whom a substantial increase in immature atypical mast cells is found, but the criteria for a primary mast cell disease (mast cell leukemia or systemic mastocytosis) are not fulfilled (1–5). Typically, patients with myelomastocytic leukemia exhibit an increase in blast cells as well as >10% metachromatic cells in peripheral blood and/or bone marrow smears (3–5). Blast cells are myeloblasts by morphologic and immunophenotypic criteria. These patients are thus diagnosed to have an advanced myelodysplastic syndrome with excess of blasts, a myeloproliferative disease, or an acute myeloid leukemia (AML; refs. 1–4). Myelomastocytic leukemia is a rare disease. In fact, <5% of all patients with myelodysplastic syndrome, myeloproliferative disease, or AML are considered to develop a "mastocytic transformation" (3, 4).

Metachromatic cells in myelomastocytic leukemia are immature, often exhibit a blast-like morphology, and are mast cell lineage cells by electron microscopic and immunophenotypic criteria (CD117+, tryptase+, CD11b–, and CD123–; refs. 3, 4). Mature mast cells may be seen occasionally. As in other patients with myelodysplastic syndrome, myeloproliferative disease, or AML, major signs of dysplasia may be found in erythroid and granulomonocytic cells (1–3). The bone marrow histology shows a diffuse spread of metachromatic cells (1–6), whereas multifocal aggregates of tryptase-positive mast cells, typically seen in patients with systemic mastocytosis (6, 7), are not found (1–6). Other criteria of systemic mastocytosis (6) are also not met. In fact, mast cells are CD2 negative and CD25 negative and do not exhibit transforming mutations at codon 816 of c-kit (1–6). Thus, a number of diagnostic criteria are available that discriminate between myelomastocytic leukemia and a primary mast cell disease (i.e., mast cell leukemia or systemic mastocytosis; refs. 8–11).

The prognosis of patients suffering from myelomastocytic leukemia seems grave (1–6). Similar to "true" mast cell leukemia, most patients survive only a few months (1–6). However, complete remission (CR) in response to polychemotherapy has been reported (2). This is of particular interest, because patients with mast cell leukemia or aggressive systemic mastocytosis are usually not entering CR in response to polychemotherapy (6, 10, 12–15).

Thus far, little is known about the pathogenesis of myelomastocytic leukemia (3, 4). In all cases reported thus far, a complex karyotype (without specific or recurrent cytogenetic aberrations) has been described (1–5). However, many questions concerning the origin and uncontrolled growth of mast cells remain open. One most important hitherto unresolved question was whether mast cells in these patients belong to the leukemic (myeloid) clone. In the present article, we provide evidence for the clonal origin of mast cells from the leukemic clone in a patient with AML and myelomastocytic transformation.


   Patient and Methods
Top
 Abstract
 Patient and Methods
Results
 Discussion
 References
 
Case report. In February 2001, a 17-year-old male patient presented with fever, an abscess in his left thigh, anemia, thrombocytopenia, and a white blood count of 62,400 x 109/L. The differential count showed 1% segmented neutrophils, 1% basophils, 7% lymphocytes, 2% monocytes, 2% metamyelocytes, and 87% blasts. The bone marrow smear revealed 87% myeloblasts as well as an increase in immature mast cells (range, 7-11%). In the bone marrow trephine biopsy, a diffuse infiltration with leukemic blasts and immature mast cells (~10%), but no focal dense mast cell infiltrates, was found. Karyotyping of bone marrow mononuclear cells revealed a complex pattern including a variant t(8;21) involving chromosomes 8, 10, and 21. The reported karyotype was 46,XY, t(8;10;21)(q22;q21;q22), t(11;19)(q13;13) [30 of 50 metaphases]; 46,XY, t(8;10;21)(q22;q21;q22), t(11;19)(q13;13), del(9)(q22) [20 of 50 metaphases]. Reverse transcriptase-PCR confirmed the presence of the t(8;21)-specific fusion gene AML1/ETO. The c-kit point mutation D816V, typically found in systemic mastocytosis (6), was not detectable. The diagnosis myelomastocytic leukemia arising in AML with a complex karyotype including t(8;21) was established. The serum tryptase level was markedly elevated (745 ng/mL; normal range, <15 ng/mL).

Staining techniques and fluorescence in situ hybridization. Immunohistochemistry and flow cytometry were done to characterize neoplastic cells and to discriminate between AML blasts and immature mast cells. Expression of surface antigens was analyzed by multicolor flow cytometry on a FACScan (Becton Dickinson, San Diego, CA) using monoclonal antibodies against CD117 (YB5.B8), CD34 (581), CD2 (S5.2 and RPA-2.10), CD25 (2A3), and CD45 (2D1; all from Becton Dickinson), as described (16, 17). Immunohistochemistry was done on formalin-fixed and paraffin-embedded bone marrow sections according to published techniques (17–19) using monoclonal antibodies against CD34 (QBEND-10, Novocastra, Newcastle, United Kingdom), CD2 (AB75, Novocastra), CD25 (4C9, Novocastra), and mast cell tryptase (G3, Chemicon, Temecula, CA; refs. 17–19). For interphase fluorescence in situ hybridization (FISH), probes hybridizing to AML1 or ETO (purchased from Vysis, Inc., Downers Grove, IL) were applied on Ficoll-separated bone marrow mononuclear cells that had been dropped onto cytospin slides and then were stained with anti-tryptase monoclonal antibody G3 and an AMCA-labeled anti-mouse antibody (Vector Laboratories, Burlingame, CA). Hybridization was done as described (20, 21). Tryptase-positive and tryptase-negative cells were evaluated separately. Slides were examined under an Axioplan-2 immunofluorescence microscope (Zeiss, Jena, Germany) equipped with appropriate filters to visualize green, red, and blue immunofluorescence either separately or simultaneously. Images were captured with a cooled charge-coupled device camera (Photometrics, Tucson, AZ) mounted on the microscope and linked to an Apple Macintosh computer. Prints were obtained with a Phaser 440 Tektronix color printer (Tektronix, Wilsonville, OR).

Monitoring of disease during therapy using disease-related markers. Disease-related markers were measured serially before and after therapy to define and monitor the response to therapy. AML/ETO was analyzed in bone marrow and peripheral blood mononuclear cells by reverse transcriptase-PCR as described (22). Serum tryptase levels were determined by fluoroenzyme immunoassay (Pharmacia, Uppsala, Sweden; ref. 17).


   Results
Top
 Abstract
 Patient and Methods
 Results
Discussion
 References
 
Morphologic and immunophenotypic delineation of mast cells and acute myeloid leukemia blasts. As assessed by morphology and immunophenotyping, two distinct populations of neoplastic cells were detected in the bone marrow (i.e., AML blasts and immature mast cells). AML blasts showed a prominent nucleus with fine nuclear chromatin and a basophilic cytoplasm without metachromatic granules (Fig. 1A). Phenotypically, blasts were CD34+, CD117+, and tryptase negative (Table 1). Mast cells were small to medium sized with a pale cytoplasm containing few or numerous metachromatic granules and a round or bilobed nucleus (Fig. 1A). By morphologic examination alone, it was impossible to define whether these cells were mast cells or basophils. As assessed by flow cytometry, these cells were found to express tryptase and CD117 confirming the mast cell lineage but did not express CD34, CD2, or CD25 (Fig. 1B; Table 1). Identical results were obtained by immunohistochemistry. Figure 1C shows expression of tryptase in diffusely spread mast cells. Compact infiltrates of tryptase-positive cells (typically found in systemic mastocytosis) were not detected in bone marrow sections.



View larger version (44K):
[in this window]
[in a new window]
  		Fig. 1. Morphology and phenotype of neoplastic cells. A, a bone marrow smear was stained by Wright Giemsa. Blast cells were found to contain a prominent nucleus and a basophilic cytoplasm without metachromatic granules. Mast cells appeared to be immature with few or numerous metachromatic granules and often contained a bilobed nucleus. B, flow cytometric analysis of expression of CD34, CD2, and CD25 on CD117+ neoplastic mast cells. The mIgG1 control is also shown. C, immunohistochemical staining for tryptase in a bone marrow section obtained at diagnosis.

 

View this table:
[in this window]
[in a new window]
  		Table 1. Expression of mast cell–related markers

 
Demonstration that mast cells and acute myeloid leukemia blasts belong to the same clone. To study clonality of blast cells and mast cells, FISH analysis with probes specific for the t(8;21)(q22;q22) were done on tryptase-stained bone marrow cells. In these experiments, AML1/ETO cohybridization signals indicating a t(8;21) were observed in 61% of all tryptase-negative blast cells examined (100 cells evaluated). In addition, AML1/ETO cohybridization signals were detected in 94% (47 of 50) of all tryptase-positive mast cells analyzed (Fig. 2). Thus, the leukemia-specific chromosomal aberration was present both in AML blasts and the immature tryptase-positive mast cells.



View larger version (27K):
[in this window]
[in a new window]
  		Fig. 2. FISH analysis of myeloblasts and mast cells. Bone marrow cells were spun on cytospin slides and stained with anti-tryptase mAb G3 (blue). Cells were examined for the presence of the AML1/ETO fusion gene using AML1-specific probe (green) and ETO-specific probe (red). AML1/ETO was identified in tryptase-positive mast cells (arrowheads) as well as in tryptase-negative AML blasts.

 
Response to therapy and monitoring of disease-related variables. In response to induction chemotherapy (daunorubicin, 45 mg/m2/d, days 1-3; etoposide, 100 mg/m2/d, days 1-5, and cytarabine, 100 mg/m2/d, days 1-7; "3 + 5 + 7 protocol"), the patient entered a hematologic CR. However, tryptase levels remained above normal range (126 ng/mL; normal range, <15 ng/mL), and immature atypical mast cells were still detectable in bone marrow smears. In addition, the AML1/ETO fusion gene product was detectable by PCR. Because of pulmonary aspergillosis requiring lobectomy and antimycotic therapy, no high-dose consolidation was administered at that time. In June 2001, a nonmyeloablative stem cell transplantation (sibling donor) was done in CR (conditioning regimen: fludarabine, 30 mg/m2/d, days –4 to –2; total body irradiation: 2 Gy on day 0). After transplantation, the tryptase level still remained elevated (73 ng/mL), immature atypical mast cells were still detectable in bone marrow smears, and the AML1/ETO PCR remained positive (Fig. 3). In August 2001, the patient relapsed. Salvage therapy (FLAG: fludarabin, 30 mg/m2/d, days 1-5; cytarabine, 2,000 mg/m2/d, days 1-5; granulocyte colony-stimulating factor, 300 µg/m2) was administered in September 2001 and led to a second CR. Then, myeloablative stem cell transplantation (same donor; conditioning regimen: busulfex, 4 x 0.8 mg/kg/d, days –7 to –4; endoxan, 2 x 60 mg/kg/d, days –3 to –2) was done (November 2001). After transplantation, the patient entered continuous CR (thus far, 742 days after transplantation). In addition, all disease-related variables (AML1/ETO, atypical bone marrow mast cells, elevated serum, and tryptase) disappeared (Fig. 3).



View larger version (18K):
[in this window]
[in a new window]
  		Fig. 3. Response to therapy. Conventional chemotherapy (DAV = 3 + 5 + 7) and nonmyeloablative stem cell transplantation (SCT) did not result in continuous CR. The serum tryptase level was still elevated (>15 ng/mL) and AML1/ETO fusion transcripts still detectable ({bullet}). However, after FLAG and myeloablative stem cell transplantation, he entered continuous CR with disappearance of mast cells, AML1/ETO ({circ}), and decrease of serum tryptase to <15 ng/mL.

 

   Discussion
Top
 Abstract
 Patient and Methods
 Results
 Discussion
References
 
Myelomastocytic leukemia is a term used for patients with advanced myeloid neoplasms (AML, myelodysplastic syndrome with excess of blasts, and chronic myelogenous leukemia blast phase), in whom elevated numbers of atypical immature mast cells are found, but the criteria for systemic mastocytosis or mast cell leukemia are not fulfilled (1–6). The current study was done to clarify whether mast cells in myelomastocytic leukemia are derived from the leukemic clone. As assessed by combined FISH and tryptase staining, both the tryptase-negative AML blasts and tryptase-positive mast cells were found to contain the t(8;21) in a patient with myelomastocytic leukemia. In response to chemotherapy and stem cell transplantation, all disease-related markers (blasts, atypical mast cells, elevated tryptase, and AML1/ETO) disappeared. These results suggest that mast cells were derived from the leukemic clone.

In previous reports describing myelomastocytic leukemia, the monoclonal origin of leukemic blasts and mast cells has already been discussed (3–5). The hypothesis was based on the histology and (immature) morphology of mast cells in these patients (3–5). Concerning the histology, the bone marrow always shows diffusely scattered mast cells infiltrating the bone marrow without dense focal infiltrates (1–5). Morphologically, mast cells are immature (blast like) or are more mature with a "promastocyte morphology" (i.e., bilobed or polylobed nuclei; refs. 1–5, 23). In our patient, mast cells were also found to be "rather mature" metachromatic cells many of which exhibited bilobed nuclei. All in all, the morphology of mast cells in our case was closely resembling the promastocyte stage of mast cell differentiation (23). Therefore, it was quite easy to differentiate between mast cells and blast cells in bone marrow smears and cytospin slides. The identity of mast cells was also confirmed by immunophenotyping.

A number of criteria have become available to differentiate between myelomastocytic leukemia and a primary mast cell disease (systemic mastocytosis or mast cell leukemia). These criteria include the histology, morphology, expression of CD2 and CD25, and the c-kit mutation D816V. In primary mast cell diseases, mast cells typically form dense infiltrates in the bone marrow histology, often are spindle-shaped cells, express CD2 and/or CD25, and exhibit c-kit D816V (5, 6, 24–26). In our patient, none of these criteria were fulfilled, so that a primary mast cell disease could be excluded. This is of particular importance, because patients with AML may also have an associated primary mast cell disease (i.e., systemic mastocytosis) and t(8;21) is frequently detected in these systemic mastocytosis/AML patients (27–29).

In primary mast cell disorders (systemic mastocytosis, mast cell leukemia), monoclonality of mast cells has been documented by the recurrent somatic c-kit mutation D816V (24, 25). It has also been described that mast cells and leukemic cells may both contain the c-kit mutation D816V and thus are of monoclonal origin in systemic mastocytosis with concordant myelomonocytic leukemia (30, 31). However, the clonality status of mast cells in patients with myelomastocytic leukemia has not been analyzed thus far. In the current study, we show by combined FISH and tryptase staining that tryptase-negative AML blasts and tryptase-positive mast cells both contain the t(8;21) in a patient with myelomastocytic leukemia. These data show that mast cells and blasts were derived from the same clone. Whether mast cells and blast cells are of monoclonal origin in all patients with myelomastocytic transformation remains at present unknown. Because of the immaturity of mast cells in most of these patients (1–5), however, the monoclonality concept seems most likely.

Thus far, only a few clinical reports have alluded to treatment options for patients with myelomastocytic leukemia. Patients receiving cytoreductive treatment and supportive care had a short survival (1). In one case with myelomastocytic leukemia, intensive polychemotherapy was administered and resulted in CR (2). Based on this knowledge and the age of our patient, we decided to apply intensive chemotherapy and stem cell transplantation. Interestingly, whereas nonmyeloablative transplantation did not result in continuous CR, myeloablative transplantation (with stem cell from the same donor) resulted in a continuous CR. The early decrease in blast cells as opposed to the persistence of mast cells after transplantation may have several explanations. First, blasts may be more sensitive to the chemotherapy applied compared with mast cells (12–15). The second possibility would be that immature mast cell progenitors but not more mature mast cells were targets of therapy. If so, any effect of chemotherapy on mast cell numbers must be expected to occur after a certain latency period because of the extremely long differentiation and life span of mast cells (months to years; ref. 32).

The serum tryptase concentration has recently been introduced as a novel marker of minimal residual disease in AML (17, 33). In the current study, the tryptase level was also employed to monitor the disease and disease response to therapy. One interesting observation was that tryptase levels showed a good correlation with "AML1/ETO positivity" and with the numbers of atypical mast cells in the bone marrow. This observation suggests that the serum tryptase level may be a reliable variable to monitor the disease in patients with myelomastocytic leukemia.

As mentioned above, mast cells are considered relatively insensitive to conventional chemotherapies (12–14). This may apply especially to primary mast cell diseases, including aggressive systemic mastocytosis and mast cell leukemia, but may apply to a degree also to myelomastocytic leukemia (12–14, 27). Still, however, there may be an important difference. In fact, based on this case and several other observations (2, 12–14, 27), it may be concluded that compared with mast cell leukemia and aggressive systemic mastocytosis, patients with myelomastocytic leukemia have a (much) better chance to be cured by aggressive chemotherapy and stem cell transplantation.

In summary, our results provide evidence that mast cells directly derive from the AML clone in myelomastocytic leukemia thereby contrasting patients with AML with coexisting systemic mastocytosis. In line with this notion, neoplastic mast cells disappeared together with AML blasts in our patient after allogeneic stem cell transplantation, which is not seen in patients with systemic mastocytosis/AML or true mast cell leukemia. Based on these notions, we believe that it is of importance to differentiate among myelomastocytic leukemia, mast cell leukemia, and systemic mastocytosis/AML.


   Acknowledgments
 
We thank Hans Semper for skillful technical assistance. This study was supported by the Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich (FWF), grant #P-14031 and #F0508 and the Austrian Federal Ministry for Education, Science and Culture, grant GZ 200.062/2-VI/1/2002.


   Footnotes
 
Grant support: Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich grants P-14031 and F0508 and the Austrian Federal Ministry for Education, Science and Culture, grant GZ 200.062/2-VI/1/2002.

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 5/16/05; revised 6/20/05; accepted 7/ 7/05.


   References
Top
 Abstract
 Patient and Methods
 Results
 Discussion
 References
 

  1. Valent P, Spanblöchl E, Bankl HC, et al. Kit ligand/mast cell growth factor-independent differentiation of mast cells in myelodysplasia and chronic myeloid leukemic blast crisis. Blood 1994;84:4322–32.[Abstract/Free Full Text]
  2. Wimazal F, Sperr WR, Horny HP, et al. Hyperfibrinolysis in a case of myelodysplastic syndrome with leukemic spread of mast cells. Am J Hematol 1999;61:66–77.[Medline]
  3. Valent P, Sperr WR, Samorapoompichit P, et al. Myelomastocytic overlap syndromes: biology, criteria, and relationship to mastocytosis. Leuk Res 2001;25:595–602.[CrossRef][Medline]
  4. Valent P, Samorapoompichit P, Sperr WR, Horny HP, Lechner K. Myelomastocytic leukemia: myeloid neoplasm characterized by partial differentiation of mast cell-lineage cells. Hematol J 2002;3:90–4.[Medline]
  5. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25:603–25.[CrossRef][Medline]
  6. Valent P, Horny HP, Li CY, et al. Mastocytosis, in Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organization classification of tumors, pathology and genetics of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001. p. 291–302.
  7. Horny HP, Valent P. Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res 2001;25:543–51.[CrossRef][Medline]
  8. Prokocimer M, Polliack A. Increased bone marrow mast cells in preleukemic syndromes, acute leukemia, and lymphoproliferative disorders. Am J Clin Pathol 1981;75:34–8.[Medline]
  9. Sperr WR, Horny HP, Lechner K, et al. Clinical and biologic diversity of leukemias occurring in patients with mastocytosis. Leuk Lymphoma 2000;37:473–86.[Medline]
  10. Sperr WR, Horny HP, Valent P. Spectrum of associated clonal hematologic non-mast cell lineage disorders occurring in patients with systemic mastocytosis. Int Arch Allergy Immunol 2002;127:140–2.[CrossRef][Medline]
  11. Bernd HW, Sotlar K, Lorenzen J, et al. Acute myeloid leukaemia with t(8;21) associated with "occult" mastocytosis. Report of an unusual case and review of the literature. J Clin Pathol 2004;57:324–8.[Abstract/Free Full Text]
  12. Travis WD, Li CY, Hoagland HC, et al. Mast cell leukemia: report of a case and review of the literature. Mayo Clin Proc 1986;61:957–66.[Medline]
  13. Worobec AS. Treatment of systemic mast cell disorders. Hematol Oncol Clin North Am 2000;14:659–87.[CrossRef][Medline]
  14. Valent P, Akin C, Sperr WR, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res 2003;27:635–41.[CrossRef][Medline]
  15. Valent P, Akin C, Sperr WR, et al. Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 2003;122:695–717.[CrossRef][Medline]
  16. Schernthaner GH, Jordan JH, Ghannadan M, et al. Expression, epitope analysis, and functional role of the LFA-2 antigen detectable on neoplastic mast cells. Blood 2001;98:3784–92.[Abstract/Free Full Text]
  17. Sperr WR, Jordan JH, Baghestanian M, et al. Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia. Blood 2001;98:2200–9.[Abstract/Free Full Text]
  18. Horny HP, Sillaber C, Menke D, et al. Diagnostic value of immunostaining for tryptase in patients with mastocytosis. Am J Surg Pathol 1998;22:1132–40.[CrossRef][Medline]
  19. Jordan JH, Walchshofer S, Jurecka W, et al. Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L). Hum Pathol 2001;32:545–52.[CrossRef][Medline]
  20. Kaufmann H, Ackermann J, Nosslinger T, et al. Absence of clonal chromosomal relationship between concomitant B-CLL and multiple myeloma-a report on two cases. Ann Hematol 2001;80:474–8.[CrossRef][Medline]
  21. Drach J, Angerler J, Schuster J, et al. Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance. Blood 1995;86:3915–21.[Abstract/Free Full Text]
  22. Kusec R, Laczika K, Knöbl P, et al. AML1/ETO fusion mRNA can be detected in remission blood samples of all patients with t(8;21) acute myeloid leukemia after chemotherapy or autologous bone marrow transplantation. Leukemia 1994;8:735–9.[Medline]
  23. Sperr WR, Escribano L, Jordan JH, et al. Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis. Leuk Res 2001;25:529–36.[CrossRef][Medline]
  24. Longley BJ, Tyrrell L, Lu SZ, et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 1996;12:312–4.[CrossRef][Medline]
  25. Longley BJ, Jr., Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A 1999;96:1609–14.[Abstract/Free Full Text]
  26. Escribano L, Orfao A, Diaz-Agustin B, et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood 1998;91:2731–6.[Abstract/Free Full Text]
  27. Sperr WR, Walchshofer S, Horny HP, et al. Systemic mastocytosis associated with acute myeloid leukaemia: report of two cases and detection of the c-kit mutation Asp-816 to Val. Br J Haematol 1998;103:740–9.[CrossRef][Medline]
  28. Chen TY, Chen JS, Huang WT, et al. Rapid engraftment of mast cells of donor origin in a case of acute myeloid leukemia with mast cell leukemia after allogeneic stem cell transplantation. Bone Marrow Transplant 2003;32:111–4.[CrossRef][Medline]
  29. Pullarkat VA, Bueso-Ramos C, Lai R, et al. Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: analysis of clinicopathologic features and activating c-kit mutations. Am J Hematol 2003;73:12–7.[CrossRef][Medline]
  30. Sotlar K, Marafioti T, Griesser H, et al. Detection of c-kit mutation Asp 816 to Val in microdissected bone marrow infiltrates in a case of systemic mastocytosis associated with chronic myelomonocytic leukaemia. Mol Pathol 2000;53:188–93.[Abstract/Free Full Text]
  31. Sotlar K, Fridrich C, Mall A, et al. Detection of c-kit point mutation Asp-816 –> Val in microdissected pooled single mast cells and leukemic cells in a patient with systemic mastocytosis and concomitant chronic myelomonocytic leukemia. Leuk Res 2002;26:979–84.[CrossRef][Medline]
  32. Födinger M, Fritsch G, Winkler K, et al. Origin of human mast cells: development from transplanted hematopoietic stem cells after allogeneic bone marrow transplantation. Blood 1994;84:2954–9.[Abstract/Free Full Text]
  33. Sperr WR, Hauswirth AW, Valent P. Tryptase a novel biochemical marker of cute myeloid leukemia. Leuk Lymphoma 2002;43:2257–61.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 haematolHome page
A. Tefferi, S. Verstovsek, and A. Pardanani
How we diagnose and treat WHO-defined systemic mastocytosis in adults
Haematologica, January 1, 2008; 93(1): 6 - 9.
[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 Sperr, W. R.
Right arrow Articles by Valent, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sperr, W. R.
Right arrow Articles by Valent, P.

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