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Home , Acute myeloid leukemia, Leukemia, Mast cell leukemia, Myelodysplastic syndrome, Myeloid leukemia

Marrow Transplantation (2003) 32, 111–114 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Case report Rapid engraftment of mast cells of donor origin in a case of myeloid with leukemia after allogeneic transplantation

T-Y Chen1, J-S Chen2, W-T Huang1, W-C Su1 and C-J Tsao1

1Division of /, Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan, Taiwan; and 2Department of Pediatrics, National Cheng-Kung University Hospital, Tainan, Taiwan

Summary: acute (AML) with MCL for which the patient received allogeneic stem cell transplantation (SCT) is a rare characterized by an for persistent mastocytosis. Interestingly, the mast cells abnormal increase of mast cells in tissues. We report a derived from the donor stem cells only 31 days after case of (AML) with t(8;21) and transplant. (MCL) in which the mastocytosis persisted after standard and allogeneic stem cell transplantation, although the myeloid leukemia Materials and methods achieved molecular complete soon after induc- tion chemotherapy. Donor-type mast cells were noted on Sequence analysis of the c- domain d31 after transplant. No c-kit was found before or after the transplant. This represents the first reported (BM) was obtained after informed consent case in which rapid engraftment of mast cells of donor was given. BM mononuclear cells (MNC) were isolated by origin was documented. Thus, the possibility that the mast Ficoll density gradient centrifugation. MNC were used for cell originates from a common myeloid may AML-ETO7 and c-kit mutation analysis. Isolation of total be questioned and a reactive process should be considered RNA, cDNA synthesis, PCR amplification and direct in some cases of systemic mastocytosis. nucleotide sequence analysis of the c-kit kinase domain Bone Marrow Transplantation (2003) 32, 111–114. extending from codon 510 to codon 626 and from codon doi:10.1038/sj.bmt.1704098 763 to 858 was performed as described.8 Keywords: mastocytosis; mast cell leukemia; c-kit recep- tor; stem cell transplantation Chimeric study Engraftment and monitoring the efficacy of SCT was assessed by detecting the chimeric status of BM MNC in Systemic mast cell disease is a disorder characterized by the recipient with the use of short tandem repeat (STR) proliferation of mast cells in various tissues. Recently, the microsatellite marker on d31 and d95. Total BM cells were WHO proposed diagnostic criteria and a classification of used for the chimeric study on d340. One STR marker systemic mastocytosis (SM). SM is divided into four (D6S442) was used, which had a high capacity between to categories: indolent SM, SM with an associated clonal discriminate recipient and donor. Their STRs were detected hematologic nonmast cell lineage disease (AHNMD), by polymerase chain reaction and were analyzed by using aggressive SM, and mast cell leukemia (MCL).1 MCL is a ABI310 Genetic Analyzer (Applied Biosystem, Foster City, high-grade (malignant) mast cell disease with circulating CA, USA) and GeneScan software. MC and a very unfavorable . Differentiation of human MCs can be induced in vitro from c-kit+, CD34+ colony-forming cells and stem cell factor (SCF).2 Two c-kit Case report (Val560Gly and Asp816Val) located in the tyrosine kinase domain have been reported in the human An 18-year-old man presented in July 2001 with and MCL cell line HMC-1.3 One of them, Asp816Val, has been . His white cell count (WBC) 9 found more recently in patients with mastocytosis4,5 and was 32.6 Â 10 /l. The differential count showed 71% causes constitutional phosphorylation and ligand-indepen- 8% segmented , 1% , dent activation of c-kit.3,6 We recently observed a case of 12% , and 8% mast cells. The BM smear revealed 37.5% myeloblasts and dense mast cell infiltration (40% of all nucleated cells). Some mast cells showed bi- or multi-lobulated nuclei (Figure 1a). There were no mediator- Correspondence: Dr T-Y Chen, Division of Hematology/Oncology, Department of Internal Medicine, National Cheng-Kung University related symptoms or skin lesions present. The mast cells Hospital, 138 Sheng-Li Road, Tainan 704, Taiwan stained positive for CD117, tryptase, chloroacetate-esterase Received 6 September 2002; accepted 9 January 2003 and toluidine blue. A diagnosis of AML-M2 was estab- Donor origin of mast cells in mastocytosis T-Y Chen et al 112

Figure 1 Various aspects of abnormal mast cells: bilobular (a) and spindle-shape (b).

lished according to FAB criteria. Cytogenetic studies showed t(8;21) (q22;q22). Induction chemotherapy (ida- rubicin, 12 mg/m2/day, days 1–3; , 100 mg/m2/ day, days 1–7) (‘3+7 protocol’) was administered. The patient entered complete remission with disappearance of peripheral mast cells, but BM mastocytosis (27.5%) persisted. He received one course of consolidation che- motherapy in August. Since persistent mastocytosis and hepatosplenomegaly, he received allogeneic peripheral Figure 2 Chimeric study. Recipient before SCT (a) donor (b) and d31 blood SCT from his brother in December 2001. The after SCT (c). conditioning regimen consisted of 16 mg/kg and 120 mg/kg . and cyclos- tive syndromes. Some suggest that the two cell types come porin-A were administered as graft-versus-host disease from a common myeloid precursor, then transform to (GVHD) prophylaxis. His absolute count was leukemic blast or mast cells. In our patient, the initial 0.5 Â 109/l on d14 and count over 20 Â 109/l on d20. diagnosis was AML with t(8;21) associated with BM and On d31 after PBSCT, he showed complete hematopoietic peripheral mastocytosis. Interestingly, BM mastocytosis recovery. We performed BM studies and still found a dense persisted through the entire clinical course, when molecular mast cell infiltration (40%) with some spindle-shaped mast complete remission was achieved, and even when donor cells (Figure 1b). stem cells were the apparent source of MCs after SCT. The We analyzed the transcript of AML-ETO at diagnosis, hypothesis of a reactive MC process would be in line with after induction chemotherapy, and after SCT. The AML- the observation that the MC genotype switched from ETO transcript could be seen on diagnosis; it disappeared recipient to donor. Donor-type mastocytosis after SCT had after induction chemotherapy. The analysis proved that the been reported by Fodinger et al.9 They proved MCs derived patient entered molecular remission after induction. A c-kit in vivo from the earliest BM hematopoietic progenitor cells. mutation analysis found there was no Asp820Gly mutation. In their case, the enriched MCs were the recipient genotype No other c-kit mutation could be found in codon 510–626 3 months after BM transplantation, but showed the donor and codon 763–858, before or after SCT. Chimerism studies genotype 6 months after transplant. In our patient, the were performed on d31, d95 and d340, and a total donor MCs displayed the donor genotype immediately after genotype was first noted after d31 (Figure 2). This proved engraftment. Fodinger et al considered that recurrence of indirectly that the mast cells after SCT were derived from clonal disease of donor origin after BMT should be donor hematopoietic stem cells. Now the patient is 370 days excluded by further genetic study and concluded that the after transplantation and still has and hepa- development of human MCs in vivo from their precursor tosplenomegaly. No GVHD was observed during the course. cells seem to be a prolonged process. Development and differentiation of human MCs in vitro (with SCF as ) takes about 4–10 weeks.2,10,11 In our patient, Discussion however, the time for differentiation (only 31 days) was shorter than theirs and comparable to the in vitro studies. A number of studies have suggested an association between Owing to the short interval, a reactive process was more BM mastocytosis and myelodysplastic or myeloprolifera- favored. The only difference between their patient and ours

Bone Marrow Transplantation Donor origin of mast cells in mastocytosis T-Y Chen et al 113 is the origin of hematopoietic stem cells used for heterogeneous disease and allow guidance concerning transplantation. We used peripheral hematopoietic stem prognosis and targeted therapies. cells, in contrast to BM stem cells. Interestingly, we found no c-kit mutation among codon 510–626 and codon 763– 858. There must be an unknown mechanism in the BM microenvironment which induced mastocytosis, and this Acknowledgements mechanism was refractory to chemotherapy, and even We thank to Dr P Valent, Department of Internal Medicine I, allogeneic SCT. University of Vienna, Austria for valuable assistance. Since BM mononuclear cells were used for the chimeric studies on d31 and d95, mast cells may not be in the mononuclear fraction. We therefore used unfractionated BM cells for the chimeric study on d340, and full donor References type could still be seen. This proved, although indirectly, that the mast cells were derived from the donor on d340. 1 Valent P, Horny HP, Escribano L et al. Diagnostic criteria and Inbred mutant mice represent useful tools for studying classification of mastocytosis: a consensus proposal. Leuk Res mast cell biology in transplantation experiments. There are 2001; 25: 603–625. v 2 Kirshenbaum AS, Kessler SW, Goff JP et al. Demonstration two strains of mice with MC deficiency. In W/W mice, of the origin of human mast cells from CD34+ bone marrow both the and the MC deficiency can be cured by progenitor cells. J Immunol 1991; 146: 1410–1415. infusion of bone marrow from a wild-type donor, whereas 3 Furitsu T, Tsujimura T, Tono T et al. Identification of this is not the case in Sl/Sld mice.12 From these experiments, mutations in the coding sequence of the proto- c-kit it was suggested that the mast cell deficiency in the W/Wv in a human mast cell leukemia cell line causing ligand- mice might be because of an intrinsic abnormality of BM- independent activation of c-kit product. J Clin Invest 1993; derived MC precursors. This condition is now known as c- 92: 1736–1744. kit deficiency. The MC deficiency in the Sl/Sld mice was 4 Longley BJ, Tyrrell L, Lu S et al. Somatic c-kit activating presumed to be the result of an abnormality in the mutation in and aggressive mastocytosis: Nat microenvironment required for MC differentiation. This establishment of clonality in a human mast cell . Genet 1996; 12: 312–314. has now been determined to be a deficiency of SCF, which 5 Nagata H, Worobec AS, Oh CK et al. Identification of a point is the ligand for c-kit. There is another MC-deficient mouse mutation in the catalytic domain of the protooncogene c-kit in strain with homozygous mutations at the microphthalmia peripheral blood mononuclear cells of patients who have (mi) .13 In these mice, the MCs are unresponsive to mastocytosis with an associated hematologic disorder. Proc proliferative stimuli because of defects in the regulation of Natl Acad Sci USA 1995; 92: 10560–10564. c-kit expression.14 Since our patient had no known c-kit 6 Kitayama H, Kanakura Y, Furitsu T et al. Constitutively mutation and donor origin MCs after SCT, the cause of activating mutations of c-kit receptor tyrosine kinase mastocytosis may be not because of constitutional activa- confer factor-independent growth and tumorigenicity of tion of c-kit. Uncontrollable production of SCF from the factor-dependent hematopoietic cell lines. Blood 1995; 85: microenvironment may be the cause of the mastocytosis in 790–798. 7 van Dongen HM, Macintyre EA, Gabert JA et al. Standar- our patient. dized RT-PCR analysis of fusion gene transcripts from Despite significant advances in research on mastocytosis, aberrations in acute leukemia for detection of curative treatment is not yet available. Treatment of . Leukemia 1999; 13: 1901–1928. patients who have SM with AHNMD entails individualized 8 Fritsche-Polanz R, Jordan JH, Feix A et al. Mutation analysis management of MC-mediated symptoms and signs relevant of c-kit in patients with myelodysplastic syndromes without to specific organ systems as in indolent patients. Che- mastocytosis and cases of systemic mastocytosis. Br J motherapy has often been seen to have a greater effect on Haematol 2001; 113: 357–364. the associated , and little or no effect on 9 Fodinger M, Fritsch G, Winkler K et al. Origin of human mast mast cell disease. Hematopoietic SCT does not seem to cells: development from transplanted hematopoietic stem cells Blood offer more hope as a treatment strategy in mastocytosis. after allogeneic bone marrow transplantation. 1994; 84: 2954–2959. We reviewed the peer-reviewed published literature and 10 Valent P, Spanblochl E, Sperr W et al. Induction of found only three SM patients with AHNMD who had differentiation of human mast cells from bone marrow and 9,15,16 undergone allogeneic SCT. In two of the cases, peripheral blood mononuclear cells by recombinant human although the associated hematologic disorder seemed to stem cell factor /kit ligand in long term culture. Blood 1992; 80: have resolved, mastocytosis persisted. Only one patient 2237–2245. entered remission with disappearance of all the BM MCs 11 Rottem M, Okada T, Goff JP et al. Mast cells cultured from after allogeneic SCT, for more than 24 months. Except in the peripheral blood of normal donors and patients with one case mentioned previously, the origin of MC after SCT mastocytosis originate form a CD34+/Fc epsilon RI-cell was not disclosed. Our case is the first reported case in population. Blood 1994; 84: 2489–2496. which the donor origin of MCs was documented immedi- 12 Galli SJ, Kitamura Y. Animal model of human disease. Genetically mast-cell-deficient W/Wv and Sl/Sld mice. Am J ately after engraftment. Pathol 1987; 127: 191–198. Our observations suggest that not all cases of SM are 13 Steingrimsson E, Moore KJ, Lamoreux ML et al. Molecular clonal and some may be reactive, especially in cases without basis of mouse microphthalmia (mi) mutations helps explain a c-kit clonal mutation. Further investigations may provide their developmental and phenotypic consequences. Nat Genet additional insight in to the molecular basis of this 1994; 8: 256–263.

Bone Marrow Transplantation Donor origin of mast cells in mastocytosis T-Y Chen et al 114 14 Ebi Y, Kanakura Y, Jippo-Kanemoto T et al. Low c-kit . Bone Marrow Transplant 1991; 8: expression of cultured mast cells of mi/mi genotype may be 413–415. involved in their defective responses to fibroblasts that express 16 Przepiorka D, Giralt S, Khouri I et al. Allogeneic marrow the ligand for c-kit. Blood 1992; 80: 1454–1462. transplantation for myeloproliferative disorders other than 15 Ronnov-Jessen D, Lovgreen Nielsen P, Horn T. Persistence of chronic myelogenous leukemia: review of forty cases. Am J systemic mastocytosis after allogeneic bone marrow transplan- Hematol 1998; 57: 24–28. tation in spite of complete remission of the associated

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