mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia.
mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia.
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DOI：
10.1038/s41375-023-02043-3
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发表时间：
2023-12
期刊：
影响因子：
11.4
通讯作者：
Michie, Alison M.
中科院分区：
文献类型：
--
作者：
Malik, Natasha;Hay, Jodie;Almuhanna, Hassan N. B.;Dunn, Karen M.;Lees, Jamie;Cassels, Jennifer;Li, Jiatian;Nakagawa, Rinako;Sansom, Owen J.;Michie, Alison M.
靶标缺失Raptor是雷帕霉素复合物1（MTORC1）的机械靶标的组成部分（MTORC1），它揭示了MTORC1在CLL模型中白血病的启动/维持性白血病中的重要作用，这是由于造成血肿/祖细胞（HSPCS）的失败而导致的。到B细胞谱系。在侵略性的CLL样疾病模型中，CLL样疾病负荷的减少和生存率显着增加。具有更侵略性的疾病。 MTORC1，通过诱导EEF2T56磷酸化导致EEF2失活，至少通过调节EEF2K/EEF2磷酸化和表达，蛋白质合成并抑制了mcl1，cyclin a a和cyclin a propll抑制剂治疗原代患者CLL细胞。 D2我们的研究强调了翻译伸长的重要性，作为疾病进展的驱动阻止CLL进程的新型热目标。
Targeted deletion of Raptor, a component of mechanistic target of rapamycin complex 1 (mTORC1), reveals an essential role for mTORC1 in initiation/maintenance of leukemia in a CLL model, resulting from a failure for haemopoietic stem/progenitor cells (HSPCs) to commit to the B cell lineage. Induction of Raptor-deficiency in NSG mice transplanted with Mx1-Raptor CLL progenitor cells (PKCα-KR-transduced HSPCs) after disease establishment revealed a reduction in CLL-like disease load and a significant increase in survival in the mice. Interestingly in an aggressive CLL-like disease model, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive disease. Rapamycin, but not ibrutinib, efficiently targeted the eEF2/eEF2K translation elongation regulatory axis, downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2T56 phosphorylation. mTOR inhibitor treatment of primary patient CLL cells halted proliferation, at least in part through modulation of eEF2K/eEF2 phosphorylation and expression, reduced protein synthesis and inhibited expression of MCL1, Cyclin A and Cyclin D2. Our studies highlight the importance of translation elongation as a driver of disease progression and identify inactivation of eEF2 activity as a novel therapeutic target for blocking CLL progression.
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影响因子：
3.9
作者：
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发表时间：
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