Inhibition of Rac GTPase signaling and downstream prosurvival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia
Inhibition of Rac GTPase signaling and downstream prosurvival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia
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DOI：
10.1182/blood-2011-04-351817
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发表时间：
2011-11-10
期刊：
影响因子：
20.3
通讯作者：
Mulloy, James C.
中科院分区：
文献类型：
--
作者：
Mizukawa, Benjamin;Wei, Junping;Mulloy, James C.
小 Rho GTP 酶的 Rac 家族协调造血细胞中的多种细胞功能，包括粘附、迁移、细胞骨架重排、基因转录、增殖和存活。还发现 Rac 信号的完整性在造血系统恶性肿瘤的发生和维持过程中关键性地调节细胞功能。使用体内基因靶向方法，我们证明在 MLL-AF9 白血病发生的逆转录病毒表达模型中，Rac2（而非 Rac1）对于急性髓系白血病的起始至关重要。然而，Rac1 或 Rac2 的缺失足以损害转化的 MLL-AF9 白血病的存活和生长。已知 Rac2 可以积极调节 Bcl-2 家族蛋白的表达，以实现生存平衡。我们证明，抗凋亡 Bcl-2 蛋白对下游生存信号的破坏与介导 MLL-AF9 白血病中 Rac2 缺陷的影响有关。事实上，Bcl-xL 的过度表达能够挽救 Rac2 缺陷的影响，并且 MLL-AF9 细胞对 BH3 模拟物 ABT-737 对 Bcl-2 家族蛋白的直接抑制非常敏感。此外，同时暴露于 NSC23766（一种 Rac 激活的小分子抑制剂）会增加 ABT-737 的凋亡作用，表明 Rac/Bcl-2 存活途径可能具有协同作用。 （血。2011；118(19):5235-5245）
The Rac family of small Rho GTPases coordinates diverse cellular functions in hematopoietic cells including adhesion, migration, cytoskeleton rearrangements, gene transcription, proliferation, and survival. The integrity of Rac signaling has also been found to critically regulate cellular functions in the initiation and maintenance of hematopoietic malignancies. Using an in vivo gene targeting approach, we demonstrate that Rac2, but not Rac1, is critical to the initiation of acute myeloid leukemia in a retroviral expression model of MLL-AF9 leukemogenesis. However, loss of either Rac1 or Rac2 is sufficient to impair survival and growth of the transformed MLL-AF9 leukemia. Rac2 is known to positively regulate expression of Bcl-2 family proteins toward a prosurvival balance. We demonstrate that disruption of downstream survival signaling through antiapoptotic Bcl-2 proteins is implicated in mediating the effects of Rac2 deficiency in MLL-AF9 leukemia. Indeed, over-expression of Bcl-xL is able to rescue the effects of Rac2 deficiency and MLL-AF9 cells are exquisitely sensitive to direct inhibition of Bcl-2 family proteins by the BH3-mimetic, ABT-737. Furthermore, concurrent exposure to NSC23766, a small-molecule inhibitor of Rac activation, increases the apoptotic effect of ABT-737, indicating the Rac/Bcl-2 survival pathway may be targeted synergistically. (Blood. 2011;118(19):5235-5245)