Development of a Novel Treatment Strategy Targeting JAK2 in Acute Myelogenous Leukemia.

Abstract 2619

Poster Board II-595

Somatic mutations in Janus kinase 2 (JAK2) gene activate JAK2/signal transducer and activator of transcriptions (STATs) signaling, leading to proliferation of hematopoietic cells. STAT3 and/or STAT5 were constitutively activated in the majority of patients with acute myelogenous leukemia (AML), although mutation of the JAK2 gene was an extremely rare event in AML. This study performed the immunohistochemichal examination to verify whether JAK2 was activated in AML (n=73, excluding acute promyelocytic leukemia) by utilizing the phosphor-specific antibody against JAK2. p-JAK2 was detectable in all cases examined, although its level varied between each patients (+, n=27; +/−, n=28; −/+, n=18). Statistical examination found that levels of p-JAK2 were correlated with leukocytosis (21.4 × 10⁶/L in patients with high p-JAK2 vs 13.8 × 10⁶/L in those with low p-JAK2, p<0.001) and lower complete remission rate (65.5% in patients with high p-JAK2 vs 83.3% in patients with low p-JAK2, p<0.02). In addition, there was a trend that high expression level of p-JAK2 was associated with poor prognosis in AML patients (median survival time 604 days in patients with high p-JAK2 vs 1431 days in those with low p-JAK2). Moreover, we found that the novel and specific inhibitor of the JAK2 kinase AZ960 potently inhibited the clonogenic growth of freshly isolated CD34⁺ AML cells from patients (n=6) with IC50 ranging from 0.01 to 0.1 mM. On the other hand, levels of p-JAK2 in CD34⁺ hematopoietic cells from healthy volunteers (n=3) were lower than those in CD34⁺AML cells, as measured by FACS, and their colony forming ability was not affected by AZ960. Furthermore, exposure of freshly isolated CD34⁺ AML cells to AZ960 (0.03–0.1 mM) induced apoptosis as assessed by induction of the cleaved forms of PARP as well as caspase 3, and downregulation of anti-apoptotic protein Bcl-xL. Taken together, JAK2 may be a promising molecular target for treatment of AML. Further studies are warranted to evaluate the efficacy of the JAK2 inhibitor in clinical settings.