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    • Further extensive FISH and molecular studies failed to

    2019-04-30

    Further extensive FISH and molecular studies failed to detect either BCR–ABL, PDGFRA, PDGFRB and FGFR1 rearrangements or NPM1 and FLT3 mutations, whereas c-KIT D816V monooxygenase was found on PB and BM mononuclear cells. Moreover, allele-specific PCR demonstrated JAK2 V617F mutation on both PB and BM polymorphonuclear cells, but JAK2 V617F allele burden was not assessed at AML diagnosis or during the subsequent course of the disease. An aggressive clinical behavior was observed. The patient was refractory to remission induction chemotherapy (cytarabine 100mg/m on days 1–7 and daunorubicin 45mg/m on days 1–3) and subsequent salvage chemotherapeutic FLAG regimen (fludarabine 30mg/m and cytarabine 2g/m on days 1–5, G-CSF, 5mcg/kg/day from day −1 to day +5). Thereafter, he received best supportive care and was lost of follow-up. To the best of our knowledge, we have described here the first case of AML with RUNX1–MECOM fusion transcripts and concurrent JAK2 V617F and c-KIT D816V mutations, showing marked peripheral and BM eosinophilia. AML with eosinophilia is usually found in core binding factor (CBF) leukemias, with cytogenetic abnormalities such as inv(16)(p13q22)/t(16;16)(p13;q22) resulting in CBFB–MYH11 fusion transcript or t(8;21)(q22;q22) resulting in RUNX1–RUNX1T1 fusion transcript. However, it is also rarely associated with other translocations such as t(16;21)(q24;q22), which produces the RUNX1–CBFA2T3 fusion transcript . Of interest, c-KIT mutations are documented in approximately 25–30% of cases of CBF leukemia, whereas they are infrequent in other AML subtypes . It has also recently been reported that patients with t(8;21)-positive AML showed one or two additional gene mutations in up to 50% or 15% of the cases, respectively . The most common mutated genes, in that series, were c-KIT (23/139 patients; 16.5%), NRAS (18/139 patients; 12.9%) and ASXL1 (16/139 patients; 11.5%), but also FLT3, CBL, KRAS, IDH2 and JAK2 were mutated in 2.9–5% of the cases . Of note, our patient was previously observed, a few months before AML diagnosis, because of persisting homogeneous splenomegaly and increased LDH, which, in the absence of any other features suspected for hematologic malignancy, except for a mild increase of morphologically normal basophils, were initially attributed to both minor β-thalassemia and previous acute myocardial infarction. However, based upon the retrospective analysis of the clinical features combined with the documentation of both JAK2 V617F and c-KIT D816V mutations on PB and BM samples at AML diagnosis, an aggressive leukemic transformation with eosinophilia and t(3;21)(q26;q22) translocation of a previously unrecognized MPN, rather than the occurrence of a AML, may be hypothesized in our case . Unfortunately, PB samples adequate for molecular examinations were not stored in April 2013, so we could not retrospectively investigate the presence of JAK2 and KIT mutations at first patient׳s observation. In the absence of available samples for BM morphological examinations or cytogenetic/molecular analyses before AML diagnosis, we cannot have confirmation of a potential MPN diagnosis preceding AML. Furthermore, neither JAK2 V617F allele burden at different time-points nor JAK2 V617F mutation analysis on purified myeloid blasts were available, so that we cannot exclude that such mutation would have been limited to polymorphonuclear cells. Of note, the latter possibility would not be surprising, because it has previously been reported that leukemic blasts are frequently negative for the JAK2 V617F mutation in transformed JAK2 V617F-positive MPN . The unusual clinical picture of our patient may suggest the need to perform either BM morphological examinations or cytogenetic/molecular analyses, at least on PB samples, to rule out MPN in similar cases observed for persisting/worsening splenomegaly and increased LDH, even in the absence of significant morphological and immunophenotypic abnormalities on PB. Furthermore, we have reported the association of AML with eosinophilia with another chromosomal translocation involving RUNX1, located at 21q22 region, suggesting the need to further investigate molecular mechanisms underlying the presence of abnormal eosinophilia in hematologic malignancies.