sign in sign up
<<
Home , Acute myeloid leukemia, Leukemia, Mast cell leukemia, Myelodysplastic syndrome, Myeloid leukemia

Human Biology

Myelomastocytic : Evidence for the Origin of Mast Cells from the Leukemic and Eradication by Allogeneic Transplantation Wolfgang R. Sperr,1Johannes Drach,2 Alexander W. Hauswirth,1Jutta Ackermann,2 Margit Mitterbauer,3 Gerlinde Mitterbauer,4 Manuela Foedinger,4 Christa Fonatsch,5 Ingrid Simonitsch-Klupp,6 Peter Kalhs,3 and Peter Valent1

Abstract Purpose: Myelomastocytic leukemia is a term used for patients with advanced myeloid , in whom elevated numbers of immature atypical mast cells are found, but criteria for a primary 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 with a complex 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/. Results: As assessed by in situ fluorescence hybridization combined with tryptase , both the tryptase-negative blast cells and the tryptase-positive mast cells were found to con- tain the t(8;21)-specific AML1/ETO fusion . Myeloablative stem cell transplantation resulted in complete 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 cytic leukemia is a rare disease. In fact, <5% of all patients with advanced myeloid neoplasms, in whom a substantial increase , myeloproliferative disease, or AML in immature atypical mast cells is found, but the criteria for a are considered to develop a ‘‘mastocytic transformation’’ (3, 4). primary mast cell disease ( or systemic Metachromatic cells in myelomastocytic leukemia are im- mastocytosis) are not fulfilled (1–5). Typically, patients with mature, often exhibit a blast-like morphology, and are mast myelomastocytic leukemia exhibit an increase in blast cells as cell lineage cells by electron microscopic and immunopheno- well as >10% metachromatic cells in peripheral and/or typic criteria (CD117+, tryptase+, CD11bÀ, and CD123À; refs. marrow smears (3–5). Blast cells are by 3, 4). Mature mast cells may be seen occasionally. As in other morphologic and immunophenotypic criteria. These patients patients with myelodysplastic syndrome, myeloproliferative are thus diagnosed to have an advanced myelodysplastic disease, or AML, major signs of may be found syndrome with excess of blasts, a myeloproliferative disease, in erythroid and granulomonocytic cells (1–3). The bone or an (AML; refs. 1–4). Myelomasto- 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 Authors’ Affiliations: 1Department of Internal Medicine I, Division of (6, 7), are not found (1–6). Other criteria of systemic and Hemostaseology; 2Department of Internal Medicine I, Division of -the mastocytosis (6) are also not met. In fact, mast cells are Center of Excellence in Clinical and Experimental Oncology (CLEXO); 3Department CD2 negative and CD25 negative and do not exhibit trans- 4 of Internal Medicine I, Division of Bone MarrowTransplantation; Clinical Institute of forming at codon 816 of c- (1–6). Thus, a Medical and Chemical Laboratory Diagnostics; 5Institute of Medical Biology; and 6Institute for Clinical , Medical University ofVienna, Austria number of diagnostic criteria are available that discriminate Received 5/16/05; revised 6/20/05; accepted 7/7/05. between myelomastocytic leukemia and a primary mast Grant support: Fonds zur Fo« rderung der Wissenschaftlichen Forschung in cell disease (i.e., mast cell leukemia or systemic mastocytosis; O« sterreich grants P-14031 and F0508 and the Austrian Federal Ministry for refs. 8–11). Education, Science and Culture, grant GZ 200.062/2-VI/1/2002. The of patients suffering from myelomastocytic 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 leukemia seems grave (1–6). Similar to ‘‘true’’ mast cell with 18 U.S.C. Section 1734 solely to indicate this fact. leukemia, most patients survive only a few months (1–6). Requests for reprints: Wolfgang R. Sperr, Department of Internal Medicine I, However, complete remission (CR) in response to polychemo- Division of Hematology and Hemostaseology, Medical University of Vienna, therapy has been reported (2). This is of particular interest, Wa« hringer Gu« rtel 18-20, A-1090 Vienna, Austria. Phone: 43-1-404-6085; Fax: 43-1-402-6930; E-mail: [email protected]. because patients with mast cell leukemia or aggressive systemic F 2005 American Association for . mastocytosis are usually not entering CR in response to doi:10.1158/1078-0432.CCR-05-1064 polychemotherapy (6, 10, 12–15).

www.aacrjournals.org 6787 Clin Cancer Res 2005;11(19) October 1, 2005 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research. Human Cancer Biology

Thus far, little is known about the pathogenesis of myelo- in and peripheral blood mononuclear cells by reverse mastocytic leukemia (3, 4). In all cases reported thus far, a transcriptase-PCR as described (22). Serum tryptase levels were complex karyotype (without specific or recurrent cytogenetic determined by fluoroenzyme immunoassay (Pharmacia, Uppsala, aberrations) has been described (1–5). However, many Sweden; ref. 17). questions concerning the origin and uncontrolled growth of Results mast cells remain open. One most important hitherto unresolved question was whether mast cells in these patients Morphologic and immunophenotypic delineation of mast cells belong to the leukemic (myeloid) clone. In the present article, and acute myeloid leukemia blasts. As assessed by morphology we provide evidence for the clonal origin of mast cells from the and , two distinct populations of neo- leukemic clone in a patient with AML and myelomastocytic plastic cells were detected in the bone marrow (i.e., AML blasts transformation. and immature mast cells). AML blasts showed a prominent nucleus with fine nuclear chromatin and a basophilic cyto- Patient and Methods plasm without metachromatic granules (Fig. 1A). Pheno- typically, blasts were CD34+, CD117+, and tryptase negative Case report. In February 2001, a 17-year-old male patient (Table 1). Mast cells were small to medium sized with a pale presented with , an abscess in his left thigh, , thrombo- cytoplasm containing few or numerous metachromatic gran- cytopenia, and a white blood count of 62,400 Â 109/L. The differential count showed 1% segmented , 1% , ules and a round or bilobed nucleus (Fig. 1A). By morphologic 7% , 2% , 2% metamyelocytes, and 87% examination alone, it was impossible to define whether these blasts. The bone marrow smear revealed 87% myeloblasts as well as cells were mast cells or basophils. As assessed by flow an increase in immature mast cells (range, 7-11%). In the bone cytometry, these cells were found to express tryptase and marrow trephine , a diffuse infiltration with leukemic blasts CD117 confirming the mast cell lineage but did not express and immature mast cells (f10%), but no focal dense mast cell CD34, CD2, or CD25 (Fig. 1B; Table 1). Identical results were infiltrates, was found. Karyotyping of bone marrow mononuclear cells obtained by immunohistochemistry. Figure 1C shows expres- revealed a complex pattern including a variant t(8;21) involving sion of tryptase in diffusely spread mast cells. Compact 8, 10, and 21. The reported karyotype was 46,XY, infiltrates of tryptase-positive cells (typically found in systemic t(8;10;21)(q22;q21;q22), t(11;19)(q13;13) [30 of 50 ]; mastocytosis) were not detected in bone marrow sections. 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 Demonstration that mast cells and acute myeloid leukemia the t(8;21)-specific fusion gene AML1/ETO. The c-kit point blasts belong to the same clone. To study clonality of blast cells D816V, typically found in systemic mastocytosis (6), was not and mast cells, FISH analysis with probes specific for the detectable. The diagnosis myelomastocytic leukemia arising in t(8;21)(q22;q22) were done on tryptase-stained bone marrow AML with a complex karyotype including t(8;21) was established. cells. In these experiments, AML1/ETO cohybridization signals The serum tryptase level was markedly elevated (745 ng/mL; normal indicating a t(8;21) were observed in 61% of all tryptase- range, <15 ng/mL). negative blast cells examined (100 cells evaluated). In addition, Staining techniques and fluorescence in situ hybridization. Immu- AML1/ETO cohybridization signals were detected in 94% nohistochemistry and were done to characterize (47 of 50) of all tryptase-positive mast cells analyzed (Fig. 2). neoplastic cells and to discriminate between AML blasts and immature Thus, the leukemia-specific chromosomal aberration was mast cells. Expression of surface was analyzed by multicolor flow cytometry on a FACScan (Becton Dickinson, San Diego, CA) using present both in AML blasts and the immature tryptase-positive monoclonal antibodies against CD117 (YB5.B8), CD34 (581), CD2 mast cells. (S5.2 and RPA-2.10), CD25 (2A3), and CD45 (2D1; all from Becton Response to therapy and monitoring of disease-related variables. Dickinson), as described (16, 17). Immunohistochemistry was done on In response to induction (, 45 mg/ formalin-fixed and paraffin-embedded bone marrow sections according m2/d, days 1-3; , 100 mg/m2/d, days 1-5, and to published techniques (17–19) using monoclonal antibodies against , 100 mg/m2/d, days 1-7; ‘‘3 + 5 + 7 protocol’’), the CD34 (QBEND-10, Novocastra, Newcastle, United Kingdom), CD2 patient entered a hematologic CR. However, tryptase levels (AB75, Novocastra), CD25 (4C9, Novocastra), and mast cell tryptase remained above normal range (126 ng/mL; normal range, <15 (G3, Chemicon, Temecula, CA; refs. 17–19). For interphase fluores- ng/mL), and immature atypical mast cells were still detectable cence in situ hybridization (FISH), probes hybridizing to AML1 or ETO in bone marrow smears. In addition, the AML1/ETO fusion (purchased from Vysis, Inc., Downers Grove, IL) were applied on Ficoll- separated bone marrow mononuclear cells that had been dropped onto gene product was detectable by PCR. Because of pulmonary cytospin slides and then were stained with anti-tryptase monoclonal requiring lobectomy and antimycotic therapy, no antibody G3 and an AMCA-labeled anti-mouse antibody (Vector high-dose consolidation was administered at that time. In June Laboratories, Burlingame, CA). Hybridization was done as described 2001, a nonmyeloablative stem cell transplantation (sibling (20, 21). Tryptase-positive and tryptase-negative cells were evaluated donor) was done in CR (conditioning regimen: , separately. Slides were examined under an Axioplan-2 immunofluores- 30 mg/m2/d, days À4toÀ2; total body irradiation: 2 Gy on cence microscope (Zeiss, Jena, Germany) equipped with appropriate day 0). After transplantation, the tryptase level still remained filters to visualize green, red, and blue immunofluorescence either elevated (73 ng/mL), immature atypical mast cells were still separately or simultaneously. Images were captured with a cooled detectable in bone marrow smears, and the AML1/ETO PCR charge-coupled device camera (Photometrics, Tucson, AZ) mounted on remained positive (Fig. 3). In August 2001, the patient relapsed. the microscope and linked to an Apple Macintosh computer. Prints Salvage therapy (FLAG: fludarabin, 30 mg/m2/d, days 1-5; were obtained with a Phaser 440 Tektronix color printer (Tektronix, 2 Wilsonville, OR). cytarabine, 2,000 mg/m /d, days 1-5; colony- 2 Monitoring of disease during therapy using disease-related markers. stimulating factor, 300 Ag/m ) was administered in September Disease-related markers were measured serially before and after therapy 2001 and led to a second CR. Then, myeloablative stem cell to define and monitor the response to therapy. AML/ETO was analyzed transplantation (same donor; conditioning regimen: busulfex,

Clin Cancer Res 2005;11(19) October 1,2005 6788 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research. Clonality of Mast Cells in Myelomastocytic Leukemia

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 mIgG1control is also shown. C, immunohistochemical staining for tryptase in a bone marrow section obtained at diagnosis.

4 Â 0.8 mg/kg/d, days À7toÀ4; endoxan, 2 Â 60 mg/kg/d, been discussed (3–5). The hypothesis was based on the days À3toÀ2) was done (November 2001). After transplan- histology and (immature) morphology of mast cells in these tation, the patient entered continuous CR (thus far, 742 days patients (3–5). Concerning the histology, the bone marrow after transplantation). In addition, all disease-related variables always shows diffusely scattered mast cells infiltrating the bone (AML1/ETO, atypical bone marrow mast cells, elevated serum, marrow without dense focal infiltrates (1–5). Morphologically, and tryptase) disappeared (Fig. 3). mast cells are immature (blast like) or are more mature with a ‘‘promastocyte morphology’’ (i.e., bilobed or polylobed nuclei; Discussion refs. 1–5, 23). In our patient, mast cells were also found to be ‘‘rather mature’’ metachromatic cells many of which exhibited Myelomastocytic leukemia is a term used for patients with bilobed nuclei. All in all, the morphology of mast cells in our advanced myeloid neoplasms (AML, myelodysplastic syndrome case was closely resembling the promastocyte stage of mast cell with excess of blasts, and chronic myelogenous leukemia blast differentiation (23). Therefore, it was quite easy to differentiate phase), in whom elevated numbers of atypical immature mast between mast cells and blast cells in bone marrow smears and cells are found, but the criteria for systemic mastocytosis or cytospin slides. The identity of mast cells was also confirmed by mast cell leukemia are not fulfilled (1–6). The current study immunophenotyping. was done to clarify whether mast cells in myelomastocytic A number of criteria have become available to differentiate leukemia are derived from the leukemic clone. As assessed by between myelomastocytic leukemia and a primary mast cell combined FISH and tryptase staining, both the tryptase- disease (systemic mastocytosis or mast cell leukemia). These negative AML blasts and tryptase-positive mast cells were found criteria include the histology, morphology, expression of CD2 to contain the t(8;21) in a patient with myelomastocytic and CD25, and the c-kit mutation D816V. In primary mast leukemia. In response to chemotherapy and stem cell trans- cell , mast cells typically form dense infiltrates in the plantation, all disease-related markers (blasts, atypical mast bone marrow histology, often are spindle-shaped cells, express cells, elevated tryptase, and AML1/ETO) disappeared. These CD2 and/or CD25, and exhibit c-kit D816V (5, 6, 24–26). In results suggest that mast cells were derived from the leukemic our patient, none of these criteria were fulfilled, so that a clone. primary mast cell disease could be excluded. This is of In previous reports describing myelomastocytic leukemia, the particular importance, because patients with AML may also monoclonal origin of leukemic blasts and mast cells has already have an associated primary mast cell disease (i.e., systemic

www.aacrjournals.org 6789 Clin Cancer Res 2005;11(19) October 1, 2005 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research. Human Cancer Biology

intensive polychemotherapy was administered and resulted in Ta b l e 1. Expression of mast cell ^ related markers CR (2). Based on this knowledge and the age of our patient, we decided to apply intensive chemotherapy and stem cell Marker Patient Mast cell Normal Normal transplantation. Interestingly, whereas nonmyeloablative trans- AML Mast leukemia* mast cells* basophils* plantation did not result in continuous CR, myeloablative blasts cells transplantation (with stem cell from the same donor) resulted CD2 ÀÀ + ÀÀ in a continuous CR. The early decrease in blast cells as opposed CD25 ÀÀ + À + to the persistence of mast cells after transplantation may have CD34 + ÀÀ À À several explanations. First, blasts may be more sensitive to the Tryptase À ++ + À/+ chemotherapy applied compared with mast cells (12–15). CD117 À ++ + À The second possibility would be that immature mast cell pro- c-kit D816V ÀÀ +/ÀÀ À genitors 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 *Data fromValent et al. (15) and Schernthaner et al. (16). extremely long differentiation and life span of mast cells (months to years; ref. 32). The serum tryptase concentration has recently been intro- mastocytosis) and t(8;21) is frequently detected in these duced as a novel marker of in AML systemic mastocytosis/AML patients (27–29). (17, 33). In the current study, the tryptase level was also In primary mast cell disorders (systemic mastocytosis, mast employed to monitor the disease and disease response to cell leukemia), monoclonality of mast cells has been therapy. One interesting observation was that tryptase levels documented by the recurrent somatic c-kit mutation D816V showed a good correlation with ‘‘AML1/ETO positivity’’ and (24, 25). It has also been described that mast cells and with the numbers of atypical mast cells in the bone marrow. leukemic cells may both contain the c-kit mutation D816V This observation suggests that the serum tryptase level may be a and thus are of monoclonal origin in systemic mastocytosis reliable variable to monitor the disease in patients with with concordant myelomonocytic leukemia (30, 31). How- myelomastocytic leukemia. ever, the clonality status of mast cells in patients with As mentioned above, mast cells are considered relatively myelomastocytic leukemia has not been analyzed thus far. insensitive to conventional (12–14). This may In the current study, we show by combined FISH and tryptase apply especially to primary mast cell diseases, including staining that tryptase-negative AML blasts and tryptase-positive aggressive systemic mastocytosis and mast cell leukemia, but mast cells both contain the t(8;21) in a patient with may apply to a degree also to myelomastocytic leukemia myelomastocytic leukemia. These data show that mast cells (12–14, 27). Still, however, there may be an important and blasts were derived from the same clone. Whether mast difference. In fact, based on this case and several other cells and blast cells are of monoclonal origin in all patients observations (2, 12–14, 27), it may be concluded that with myelomastocytic transformation remains at present compared with mast cell leukemia and aggressive systemic unknown. Because of the immaturity of mast cells in most mastocytosis, patients with myelomastocytic leukemia have a of these patients (1–5), however, the monoclonality concept (much) better chance to be cured by aggressive chemotherapy seems most likely. and stem cell transplantation. Thus far, only a few clinical reports have alluded to treatment In summary, our results provide evidence that mast cells options for patients with myelomastocytic leukemia. Patients directly derive from the AML clone in myelomastocytic receiving cytoreductive treatment and supportive care had a leukemia thereby contrasting patients with AML with coexisting short survival (1). In one case with myelomastocytic leukemia, systemic mastocytosis. In line with this notion, neoplastic mast

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 theAML1/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.

Clin Cancer Res 2005;11(19) October 1,2005 6790 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research. Clonality of Mast Cells in Myelomastocytic Leukemia

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 (.). However, after FLAG and myeloablative stem cell transplantation, he entered continuous CR with disappearance of mast cells, AML1/ETO (o), and decrease of serum tryptase to <15 ng/mL.

cells disappeared together with AML blasts in our patient Acknowledgments after allogeneic stem cell transplantation, which is not seen in patients with systemic mastocytosis/AML or true mast cell We thank Hans Semper for skillful technical assistance. This study was leukemia. Based on these notions, we believe that it is of supported by the Fonds zur Fo« rderung der Wissenschaftlichen Forschung in importance to differentiate among myelomastocytic leukemia, O¨ sterreich (FWF), grant # P-14031 and # F0508 and the Austrian Federal mast cell leukemia, and systemic mastocytosis/AML. Ministry for Education, Science and Culture, grant GZ 200.062/2-VI/1/2002.

References 1. Valent P, Spanblo« chl E, Bankl HC, et al. Kit patients with mastocytosis. Leuk 2000; nohistochemical properties of bone marrow mast ligand/mast factor-independent differ- 37:473 ^ 86. cells in systemic mastocytosis: evidence for expres- entiation of mast cells in myelodysplasia and 10. Sperr WR, Horny HP,Valent P. Spectrum of asso- sion of CD2, CD117/Kit, and bcl-x(L). Hum Pathol chronic myeloid leukemic blast crisis. Blood 1994; ciated clonal hematologic non-mast cell lineage 2001;32:545 ^ 52. 84:4322^ 32. disorders occurring in patients with systemic 20. Kaufmann H, Ackermann J, Nosslinger T, et al. 2.Wimazal F, Sperr WR, Horny HP, et al. Hyperfibrinol- mastocytosis. Int Arch Allergy Immunol 2002;127: Absence of clonal chromosomal relationship between ysis in a case of myelodysplastic syndrome with 14 0 ^ 2. concomitant B-CLL and -a report on leukemic spread of mast cells. Am J Hematol 1999; 11. Bernd HW, Sotlar K, Lorenzen J, et al. Acute mye- two cases. Ann Hematol 2001;80:474^ 8. 61:66 ^ 77. loid leukaemia with t(8;21) associated with ‘‘occult’’ 21. Drach J, Angerler J, Schuster J, et al. Interphase 3. Valent P, Sperr WR, Samorapoompichit P, et al. mastocytosis. Report of an unusual case and review fluorescence in situ hybridization identifies chromo- Myelomastocytic overlap syndromes: biology, crite- of the literature. J Clin Pathol 2004;57:324 ^ 8. somal abnormalities in plasma cells from patients with ria, and relationship to mastocytosis. Leuk Res 12. TravisWD,LiCY,HoaglandHC,etal.Mastcellleuke- of undetermined signifi- 2001;25:595 ^ 602. mia: report of a case and review of the literature. Mayo cance. Blood 1995;86:3915^21. 4.Valent P, Samorapoompichit P, Sperr WR, Horny Clin Proc1986;61:957^66. 22. Kusec R, Laczika K, Kno« bl P, et al. AML1/ETO fusion HP, Lechner K. Myelomastocytic leukemia: mye- 13. Worobec AS. Treatment of systemic mast cell dis- mRNA can be detected in remission blood samples of loid characterized by partial differentia- orders. Hematol Oncol Clin North Am 2000;14: all patients with t(8;21) acute myeloid leukemia after tion of mast cell-lineage cells. Hematol J 2002;3: 659^87. chemotherapy or autologous bone marrow transplan- 90^4. 14. Valent P,Akin C, SperrWR, et al. Aggressive system- tation. Leukemia 1994;8:735 ^ 9. 5. Valent P, Horny HP, Escribano L, et al. Diagnostic ic mastocytosis and related mast cell disorders: current 23. Sperr WR, Escribano L, Jordan JH, et al. Morpho- criteria and classification of mastocytosis: a consen- treatment options and proposed response criteria. logic properties of neoplastic mast cells: delineation sus proposal. Leuk Res 2001;25:603 ^ 25. Leuk Res 2003;27:635 ^ 41. of stages of maturation and implication for cytologi- 6. Valent P, Horny HP, Li CY, et al. Mastocytosis, in 15. Valent P, Akin C, Sperr WR, et al. Diagnosis and cal of mastocytosis. Leuk Res 2001;25: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. treatment of systemic mastocytosis: state of the art. 529^ 36. World Health Organization classification of tumors, BrJHaematol 2003;122:695^717. 24. Longley BJ, Tyrrell L, Lu SZ, et al. Somatic c-KIT pathology and genetics of tumors of haematopoietic 16. Schernthaner GH, Jordan JH, Ghannadan M, et al. activating mutation in and ag- and lymphoid tissues. Lyon: IARC Press; 2001. Expression, epitope analysis, and functional role of gressive mastocytosis: establishment of clonality in p. 291 ^ 302. the LFA-2 detectable on neoplastic mast cells. a human mast cell neoplasm. Nat Genet 1996;12: 7. Horny HP, Valent P. Diagnosis of mastocytosis: Blood 2001;98:3784 ^ 92. 312^ 4. general histopathological aspects, morphological 17. Sperr WR, Jordan JH, Baghestanian M, et al. 25. Longley BJ, Jr., Metcalfe DD, Tharp M, et al. criteria, and immunohistochemical findings. Leuk Expression of mast cell tryptase by myeloblasts in a Activating and dominant inactivating c-KIT catalytic Res 2001;25:543 ^ 51. group of patients with acute myeloid leukemia. Blood domain mutations in distinct clinical forms of human 8. Prokocimer M, Polliack A. Increased bone marrow 2001;98:2200 ^ 9. mastocytosis. Proc Natl Acad Sci U S A 1999;96: mast cells in preleukemic syndromes, acute leukemia, 18. Horny HP, Sillaber C, Menke D, et al. Diagnostic 16 09 ^ 14. and lymphoproliferative disorders. Am J Clin Pathol value of immunostaining for tryptase in patients 26. Escribano L, OrfaoA, Diaz-Agustin B, et al. Indolent 19 81;75 : 3 4 ^ 8. with mastocytosis. Am J Surg Pathol 1998;22: systemic mast cell disease in adults: immunopheno- 9. Sperr WR, Horny HP, Lechner K, et al. Clinical 113 2 ^ 4 0 . typic characterization of bone marrow mast cells and and biologic diversity of occurring in 19. Jordan JH, Walchshofer S, Jurecka W, et al. Immu- its diagnostic implications. Blood 1998;91:2731 ^ 6.

www.aacrjournals.org 6791 Clin Cancer Res 2005;11(19) October 1, 2005 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research. Human Cancer Biology

27. Sperr WR,Walchshofer S, Horny HP, et al. Systemic non-mast-cell lineage disease: analysis of clinicopath- tient with systemic mastocytosis and concomitant mastocytosis associated with acute myeloid leukae- ologic features and activating c-kit mutations. Am J chronic myelomonocytic leukemia. Leuk Res 2002; mia: report of two cases and detection of the c-kit mu- Hematol 2003;73:12 ^ 7. 26:979 ^ 84. tation Asp-816 toVal. BrJHaematol1998;103:740 ^ 9. 30. Sotlar K, Marafioti T, Griesser H, et al. Detection of 32. Fo« dinger M, Fritsch G, Winkler K, et al. Origin 28. Chen TY, Chen JS, Huang WT, et al. Rapid engraft- c-kit mutation Asp 816 to Val in microdissected bone of human mast cells: development from trans- ment of mast cells of donor origin in a case of acute marrow infiltrates in a case of systemic mastocytosis planted hematopoietic stem cells after allogeneic myeloid leukemia with mast cell leukemia after alloge- associated with chronic myelomonocytic leukaemia. bone marrow transplantation. Blood 1994;84: neic stem cell transplantation. Bone Marrow Trans- Mol Pathol 2000;53:188 ^ 93. 2954 ^ 9. plant 2003;32:111^ 4. 31. Sotlar K, Fridrich C, Mall A, et al. Detection of c-kit 33. Sperr WR, Hauswirth AW,Valent P.Tryptase a novel 29. Pullarkat VA, Bueso-Ramos C, Lai R, et al. Systemic point mutation Asp-816 ^ > Val in microdissected biochemical marker of cute myeloid leukemia. Leuk mastocytosis with associated clonal hematological pooled single mast cells and leukemic cells in a pa- Lymphoma 2002;43:2257 ^ 61.

Clin Cancer Res 2005;11(19) October 1,2005 6792 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research. Myelomastocytic Leukemia: Evidence for the Origin of Mast Cells from the Leukemic Clone and Eradication by Allogeneic Stem Cell Transplantation

Wolfgang R. Sperr, Johannes Drach, Alexander W. Hauswirth, et al.

Clin Cancer Res 2005;11:6787-6792.

Updated version Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/11/19/6787

Cited articles This article cites 32 articles, 9 of which you can access for free at: http://clincancerres.aacrjournals.org/content/11/19/6787.full#ref-list-1

Citing articles This article has been cited by 4 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/11/19/6787.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/11/19/6787. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.

Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2005 American Association for Cancer Research.