Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support
Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support
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DOI：
10.1038/sj.leu.2403560
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发表时间：
2005-01-01
期刊：
影响因子：
11.4
通讯作者：
McCubrey, JA
中科院分区：
文献类型：
--
作者：
Bertrand, FE;Spengemen, JD;McCubrey, JA
骨髓基质细胞对于正常和白血病人B系细胞的分化、存活和增殖是必需的。白血病细胞需要基质细胞支持以实现最佳增殖和抗凋亡。基质细胞接触可促进对化疗剂的抗性。在这项研究中，我们利用小分子量抑制剂和已建立的基质细胞依赖性pre-BALL细胞系BLIN-2，研究MAP激酶，PI 3 K/Akt，JAK/STAT和mTOR通路在基质细胞支持下促进白血病细胞生长的作用。用PI 3 K +JAK、PI 3 K +MEK或MEK+JAK抑制剂组合处理导致增殖抑制，如通过DNA合成所测量。然而，仅抑制PI 3 K和MEK两者或mTOR和MEK两者导致在24小时内膜联蛋白V（+）/PI+凋亡事件的数量急剧增加。我们的数据表明，B系ALL中基质细胞介导的凋亡保护是由PI 3 K/mTOR和MEK通过协同机制介导的。
Bone marrow stromal cells are essential for the differentiation, survival and proliferation of normal and leukemic human B-lineage cells. Leukemic cells require stromal cell support for optimal proliferation and apoptotic resistance. Stromal cell contact can promote resistance to chemotherapeutic agents. In this study, we have made use of small molecular weight inhibitors and an established stromal cell-dependent pre-BALL cell line, BLIN-2, to investigate the role of the MAP kinase, PI3K/Akt, JAK/STAT and mTOR pathways in the promotion of leukemic cell growth in the presence of stromal cell support. Treatment with PI3K+JAK, PI3K+MEK, or MEK+JAK inhibitor combinations resulted in an inhibition of proliferation as measured by DNA synthesis. However, only inhibition of both PI3K and MEK or both mTOR and MEK resulted in a dramatic increase in the number of annexinV(+)/PI+ apoptotic events within a 24 h period. Our data suggest that stromal cell-mediated apoptotic protection in B-lineage ALL is mediated by PI3K/mTOR and MEK via a synergistic mechanism(s).