We searched for JAK2 exon 12 mutations in patients with JAK2 (V617F)-negative myeloproliferative disorders. Seventeen patients with polycythemia vera (PV), including 15 sporadic cases and 2 familial cases, carried deletions or duplications of exon 12 in circulating granulocytes but not in T lymphocytes. Two of the 8 mutations detected were novel, and the most frequent ones were N542-E543del and E543-D544del. Most patients with PV carrying an exon 12 mutation had isolated erythrocytosis at clinical onset, unlike patients with JAK2 (V617F)-positive PV, most of whom had also elevations in white blood cell and/or platelet counts. Both patients with familial PV carrying an exon 12 mutation had an affected sibling with JAK2 (V617F)-positive PV. Thus, several somatic mutations of JAK2 exon 12 can be found in a myeloproliferative disorder that is mainly characterized by erythrocytosis. Moreover, a genetic predisposition to acquisition of different JAK2 mutations is inherited in families with myeloproliferative disorders.

Key Points• Different driver mutations have distinct effects on phenotype of myelodysplastic syndromes (MDS) and myelodysplastic/ myeloproliferative neoplasms (MDS/MPN).• Accounting for driver mutations may allow a classification of these disorders that is considerably relevant for clinical decision-making. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible. (Blood. 2014;124(9):1513-1521

We studied patients with myeloid neoplasm associated with ringed sideroblasts and/or thrombocytosis. The combination of ringed sideroblasts 15% or greater and platelet count of 450 ؋ 10 9 /L or greater was found in 19 subjects fulfilling the diagnostic criteria for refractory anemia with ringed sideroblasts (RARS) associated with marked thrombocytosis (RARS-T), and in 3 patients with primary myelofibrosis. JAK2 and MPL mutations were detected in circulating granulocytes and bone marrow CD34 ؉ cells, but not in T lymphocytes, from 11 of 19 patients with RARS-T. Three patients with RARS, who initially had low to normal platelet counts, progressed to RARS-T, and 2 of them acquired JAK2 (V617F) at this time. In female patients with RARS-T, granulocytes carrying JAK2 (V617F) represented only a fraction of clonal granulocytes as determined by X-chromosome inactivation patterns. RARS and RARS-T patient groups both consistently showed up-regulation of ALAS2 and down-regulation of ABCB7 in CD34 ؉ cells, but several other genes were differentially expressed, including PSIP1 (LEDGF), CXCR4, and CDC2L5. These observations suggest that RARS-T is indeed a myeloid neoplasm with both myelodysplastic and myeloproliferative features at the molecular and clinical levels and that it may develop from RARS through the acquisition of somatic mutations of JAK2, MPL, or other as-yetunknown genes. IntroductionWithin myeloid neoplasms, myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and peripheral cytopenia, 1 whereas myeloproliferative neoplasms (MPNs) are typically associated with overproduction of mature blood cells. 2 However, the existence of conditions with overlapping features is well established. In fact, the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues comprises the category of myelodysplastic/MPNs. 3 This category includes chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (BCR-ABL1 negative), juvenile myelomonocytic leukemia, and myelodysplastic/MPNs, unclassifiable (MDS/MPN, U). These latter have been defined as clonal conditions that at the time of initial presentation have some features supporting a diagnosis of MDS and other features more consistent with MPN. One of these conditions is the provisional entity defined as refractory anemia with ringed sideroblasts (RARS) associated with marked thrombocytosis (RARS-T). 4 Ringed sideroblasts are erythroblasts with iron-loaded mitochondria visualized by Prussian blue staining as a perinuclear ring of blue granules. 5 The iron deposited in these perinuclear mitochondria is stored in mitochondrial ferritin, which is encoded by the FTMT gene. 6 Ringed sideroblasts are the distinctive feature of sideroblastic anemias, a heterogeneous group of inherited and acquired disorders. 7,8 The presence of ringed sideroblasts in the bone marrow (BM; 15% or more) is a marker of the MDS defined as RARS. 9 Ringed sideroblasts, however, can be occasionally found also in myeloproliferative disorders su...

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