Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Blood. 2010 Apr 8;115(14):2901-9. doi: 10.1182/blood-2009-03-209544. Epub 2010 Feb 16.
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 inhibition-induced apoptosis remain unclear. In this study, we show that JAK2 inhibition-induced apoptosis correlated with up-regulation 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.
激活突变 JAK2 V617F 在真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化的发病机制中起核心作用。抑制 JAK2 活性可导致突变 JAK2 细胞的生长抑制和凋亡。然而，参与 JAK2 抑制诱导凋亡的促凋亡蛋白仍不清楚。在这项研究中，我们表明 JAK2 抑制诱导的凋亡与 JAK2 突变的造血细胞系中未磷酸化形式的 BH3 仅蛋白 Bim 的上调相关。Bim 的敲低显著抑制 JAK2 抑制诱导的凋亡，而 BH3 模拟物 ABT-737 可逆转这种抑制。此外，ABT-737 增强了 JAK2 V617F(+) HEL 和 SET-2 细胞中 JAK2 抑制诱导的凋亡。JAK 抑制剂 I 和 ABT-737 的联合使用比单独使用任一药物更有效地减少源自 JAK2 V617F(+)真性红细胞增多症患者 CD34(+)细胞的红细胞集落数量。这些数据表明 Bim 是 JAK2 抑制诱导凋亡的关键效应分子，靶向该凋亡途径可能是具有激活 JAK2 突变的患者的一种新的治疗策略。
