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Myelomastocytic Leukemia: Evidence for the Origin of Mast Cells from the Leukemic Clone and Eradication Byallogeneic Stem Cell T

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Myelomastocytic Leukemia: Evidence for the Origin of Mast Cells from the Leukemic Clone and Eradication Byallogeneic Stem Cell T 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. 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 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 con- tain 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 cytic leukemia is a rare disease. In fact, <5% of all patients with advanced myeloid neoplasms, in whom a substantial increase myelodysplastic syndrome, 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 (mast cell leukemia 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 blood and/or typic criteria (CD117+, tryptase+, CD11bÀ, and CD123À; refs. bone marrow smears (3–5). Blast cells are myeloblasts 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 dysplasia may be found syndrome with excess of blasts, a myeloproliferative disease, in erythroid and granulomonocytic cells (1–3). The bone or an acute myeloid leukemia (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 Hematology (6, 7), are not found (1–6). Other criteria of systemic and Hemostaseology; 2Department of Internal Medicine I, Division of Oncology-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 mutations at codon 816 of c-kit (1–6). Thus, a Medical and Chemical Laboratory Diagnostics; 5Institute of Medical Biology; and 6Institute for Clinical Pathology, 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 prognosis 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 Cancer Research. 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 bone marrow 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 immunophenotyping, 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 fever, an abscess in his left thigh, anemia, 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 neutrophils, 1% basophils, ules and a round or bilobed nucleus (Fig. 1A). By morphologic 7% lymphocytes, 2% monocytes, 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 biopsy, 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 chromosomes 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 metaphases]; 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 mutation 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 flow cytometry were done to characterize (47 of 50) of all tryptase-positive mast cells analyzed (Fig. 2). neoplastic
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