Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBP␣), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of Tcell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML. IntroductionAcute myeloid leukemia (AML) is a heterogeneous disease with respect to its underlying genetic abnormalities and clinical biology. 1 It has therefore been postulated that AML, although always characterized by a malignant accumulation of myeloid progenitor cells, in fact represents not a single disease, but a group of neoplasms. Cytogenetic and molecular analyses, studying specific chromosomal translocations and mutations, are used to identify subgroups of AML with distinct biologic and clinical behavior. Recent developments in microarray research have resulted in further improvements in the characterization of the molecular heterogeneity of AML, 2 and gene expression profiling (GEP) studies have demonstrated that specific chromosomal aberrations, such as the common translocations t(8;21), t(15;17), and inv(16), correlate with unique expression signatures. [3][4][5] In a GEP study of 285 cases of de novo AML, we found that specific expression profiles are associated with other recurrent genetic aberrations such as mutations in NPM1 and alterations involving MLL, and with overexpression of the proto-oncogene EVI1 as well. 4,6 Some AMLs lacking these particular abnormalities were found to express the same characteristic profiles, suggesting that deregulation of the same pathways had occurred through yet-unknown mechanisms. This study also showed that 2 distinct expression clusters (no. 4 and no. 15) consisted primarily of AML cases with mutations in CEBPA, the gene encoding the basic leucine zipper transcription factor CCAAT/enhancer-binding protein alpha (C/EBP␣). C/EBP␣ is a critical regulator of hematopoietic stem cell (HSC) homeostasis and myeloid differentiation, [7][8][9][10] and multiple studies have shown that C/EBP␣ function is frequently ...
The activating mutation JAK2 V617F plays a central role in the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2. However, the proapoptotic proteins involved in JAK2 inhibitioninduced apoptosis remain unclear. In this study, we show that JAK2 inhibitioninduced apoptosis correlated with upregulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations. Knockdown of Bim dramatically inhibited apoptosis induced by JAK2 inhibition, which was reversed by the BH3 mimetic agent ABT-737. In addition, ABT-737 enhanced the apoptosis induced by JAK2 inhibition in JAK2 V617F ؉ HEL and SET-2 cells. The combination of JAK inhibitor I and ABT-737 reduced the number of erythroid colonies derived from CD34 ؉ cells isolated from JAK2 V617F ؉ polycythemia vera patients more efficiently than either drug alone. These data suggest that Bim is a key effector molecule in JAK2 inhibition-induced apoptosis and that targeting this apoptotic pathway could be a novel therapeutic strategy for patients with activating JAK2 mutations. (Blood. 2010;115(14):2901-2909) IntroductionMyeloproliferative disorders (MPDs) are clonal hematopoietic diseases characterized by the excess production of 1 or more lineages of mature blood cells leading to complications of organomegaly, thrombosis, and hemorrhage. 1 Recently, a somatic activating mutation in Janus kinase 2 (JAK2), a nonreceptor tyrosine kinase, was identified in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). [2][3][4][5][6] A valine to phenylalanine substitution at position 617 (V617F) of JAK2 in the pseudokinase domain is the most common mutation, occurring in more than 95% of PV cases and in approximately 50% of patients with ET and PMF. 7 Other mutations, such as K539L and T875N, have been identified in a small subset of PV patients and in a megakaryoblastic leukemia cell line, CHRF-288-11 (CHRF) cells, respectively. 7 Conventional therapy for PV, ET, and PMF with cytoreductive chemotherapy or phlebotomy is not curative and does not reduce the risk of clonal evolution into myelodysplastic syndrome and acute leukemia. Thus, inhibition of mutant JAK2 may be a novel approach in the treatment of PV and other MPDs harboring JAK2 mutations. Various JAK inhibitors are currently under development and/or investigation in phase 1 and 2 clinical trials. However, initial reports from a clinical trial with one such JAK inhibitor, INCB018424, indicated that one-fourth of patients developed serious, although reversible, hematologic toxicities with initial dosing regimens. 8 Furthermore, only a modest decrease in JAK2 V617F allele burden was seen in bone marrow and peripheral blood from advanced myelofibrosis patients. 9 A phase 1 study of XL019, another JAK2 inhibitor, has shown that reversible peripheral neuropathy can occur at high doses (Ͼ 100 mg). 10 Therefor...
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