Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.

JAK2 617V>F mutation occurs in a homozygous state in 25% to 30% of patients with polycythemia vera (PV) and 2% to 4% with essential thrombocythemia (ET IntroductionPatients with Philadelphia-negative chronic myeloproliferative disorders (CMPDs) 1 harbor a recurrent mutation in the Janus tyrosine kinase 2 (JAK2) gene, consisting of a valine-tophenylalanine change at position 617 (JAK2 617VϾF) in the JH2 pseudo-kinase domain. [2][3][4][5] The JAK2 617VϾF mutation is present in the vast majority of patients with polycythemia vera (PV) 2-5 and in 40% to 60% of those with essential thrombocythemia (ET) 6-8 or myelofibrosis with myeloid metaplasia (MMM). 9,10 JAK2 617VϾF can also occasionally be detected in "atypical" MPD, myelodysplastic syndromes, chronic myelomonocytic leukemia, systemic mastocytosis, chronic neutrophilic leukemia, and eosinophilic disorders. 11-13 Mutant JAK2 is a constitutively active tyrosine kinase that confers growth factor independence in transfected hematopoietic cell lines [2][3][4][5] and is at the basis of the phenomenon of erythropoietin-independent erythroid colony (EEC) growth that is a hallmark of most PV patients and is also less frequently reported in patients with ET. 14 A key role for the "gain-of-function" 15 of mutated JAK2 in the pathogenesis of CMPD is supported by in vitro studies, which showed enhanced JAK-STAT signaling in cells bearing the mutant allele, and by in vivo animal models in which erythrocytosis 3,16 and eventually myelofibrosis 16,17 developed following transplantation of hematopoietic cells transfected with mutant JAK2 into mice.About 25% to 30% of PV and MMM patients, and 2% to 4% of ET patients, harbor the mutation in the homozygous state, a condition where at least 51% of JAK2 alleles in granulocytes are mutated as the result of a mitotic recombination process. 2-5 While a consistent number of reports have investigated the impact of the presence of 617VϾF mutation per se on the clinical and hematologic profile of CMPD patients, a few studies have specifically addressed the consequences of JAK2 617VϾF mutation when harbored in the homozygous state. 18 The complete loss of normal JAK2 allele is expected to have profound effects on cell phenotype. As a matter of fact, in cotransfection experiments, the wild-type

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Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 10/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.