Institut Cochin, Département d'Hématologie, CNRS, UMR8104, Paris.
Haematologica. 2010 May;95(5):819-28. doi: 10.3324/haematol.2009.013797. Epub 2009 Nov 30.
The PI3K/AKT and mTOR signaling pathways are activated in acute myeloid leukemia, including in the more immature leukemic populations. Constitutive PI3K activation is detectable in 50% of acute myeloid leukemia samples whereas mTORC1 is activated in all cases of this disease. In leukemic cells, the PI3K activity relates to the expression of the p110delta isoform of class IA PI3K. Constitutive PI3K activation is the result of autocrine IGF-1/IGF-1R signaling in 70% of acute myeloid leukemia samples but specific inhibition of this pathway does not induce apoptosis. Specific inhibition of PI3K/AKT or mTORC1 alone in vitro has anti-leukemic effects which are essentially exerted via the suppression of proliferation. However, as mTORC1 activation is independent of PI3K/AKT in acute myeloid leukemia, dual PI3K and mTOR inhibitors may induce apoptosis in blast cells. Moreover, mTORC1 inhibition using sirolimus overactivates PI3K/AKT via the upregulation of IRS2 expression and by favoring IGF-1/IGF-1R autocrine signaling. Recent data also indicate that mTORC1 does not control protein translation in acute myeloid leukemia. These results open the way for the design of direct inhibitors of protein synthesis as novel acute myeloid leukemia therapies and also for the development of second generation mTOR inhibitors (the TORKinhibs).
PI3K/AKT 和 mTOR 信号通路在急性髓系白血病中被激活，包括在更不成熟的白血病群体中。50%的急性髓系白血病样本中可检测到 PI3K 的组成性激活，而所有此类疾病中 mTORC1 均被激活。在白血病细胞中，PI3K 的活性与 IA 类 PI3K 的 p110delta 同工型的表达有关。在 70%的急性髓系白血病样本中，组成性 PI3K 激活是自分泌 IGF-1/IGF-1R 信号的结果，但该途径的特异性抑制不会诱导细胞凋亡。体外单独抑制 PI3K/AKT 或 mTORC1 具有抗白血病作用，其主要通过抑制增殖来发挥作用。然而，由于急性髓系白血病中 mTORC1 的激活独立于 PI3K/AKT，因此双重 PI3K 和 mTOR 抑制剂可能会诱导原始细胞凋亡。此外，使用雷帕霉素抑制 mTORC1 通过上调 IRS2 表达和促进 IGF-1/IGF-1R 自分泌信号而过度激活 PI3K/AKT。最近的数据还表明，mTORC1 不能控制急性髓系白血病中的蛋白质翻译。这些结果为设计直接的蛋白质合成抑制剂作为新型急性髓系白血病治疗方法开辟了道路，也为开发第二代 mTOR 抑制剂（TORKinhibs）铺平了道路。
