期刊
INVESTIGATIONAL NEW DRUGS
卷 29, 期 5, 页码 818-826出版社
SPRINGER
DOI: 10.1007/s10637-010-9429-z
关键词
Atiprimod; JAK inhibitor; JAK2 mutation; FDCP cells; Megakaryoblastic cells; Polycythemia vera; Myeloproliferative neoplasia
资金
- NCI NIH HHS [P30 CA016672] Funding Source: Medline
We herein report on the activity of the JAK2/JAK3 small molecule inhibitor atiprimod on mouse FDCP-EpoR cells carrying either wild-type (JAK2 (WT)) or mutant (JAK2 (V617F)) JAK2, human acute megakaryoblastic leukemia cells carrying JAK2 (V617F) (SET-2 cell line), and human acute megakaryocytic leukemia carrying mutated JAK3 (CMK cells). Atiprimod inhibited more efficaciously the proliferation of FDCP-EpoR JAK2 (V617F) (IC50 0.42 mu M) and SET-2 cells (IC50 0.53 mu M) than that of CMK (IC50 0.79 mu M) or FDCP-EpoR JAK2 (WT) cells (IC50 0.69 mu M). This activity was accompanied by inhibition of the phosphorylation of JAK2 and downstream signaling proteins STAT3, STAT5, and AKT in a dose- and time-dependent manner. Atiprimod-induced cell growth inhibition of JAK2 (V617F)-positive cells was coupled with induction of apoptosis, as evidenced by heightened mitochondrial membrane potential and caspase-3 activity, as well as PARP cleavage, increased turnover of the anti-apoptotic X-linked mammalian inhibitor of apoptosis (XIAP) protein, and inhibition of the pro-apoptotic protein BCL-2 in a time- and dose-dependent manner. Furthermore, atiprimod was more effective at inhibiting the proliferation of peripheral blood hematopoietic progenitors obtained from patients with JAK2 (V617F)-positive polycythemia vera than at inhibiting hematopoietic progenitors from normal individuals (p = 0.001). The effect on primary expanded erythroid progenitors was paralleled by a decrease in JAK2(V617F) mutant allele burden in single microaspirated BFU-E and CFU-GM colonies. Taken together, our data supports the clinical testing of atiprimod in patients with hematologic malignancies driven by constitutive activation of JAK2 or JAK3 kinases.
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