Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML.
Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML.
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抑制翻译起始因子eIF4a可使热休克因子1（HSF 1）失活，并在AML中发挥抗白血病活性。
DOI：
10.1038/s41375-021-01308-z
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发表时间：
2021-09
期刊：
影响因子：
11.4
通讯作者：
Ishizawa J
中科院分区：
文献类型：
--
作者：
Nishida Y;Zhao R;Heese LE;Akiyama H;Patel S;Jaeger AM;Jacamo RO;Kojima K;Ma MCJ;Ruvolo VR;Chachad D;Devine W;Lindquist S;Davis RE;Porco JA Jr;Whitesell L;Andreeff M;Ishizawa J
真核起始因子4A（eIF 4A）是翻译起始所必需的eIF 4F复合物的酶核心，在蛋白质合成的致癌重编程中起关键作用，因此是癌症的假定治疗靶点。作为其抗癌活性的重要组成部分，抑制翻译起始可以减轻HSF 1的致癌激活，HSF 1是一种能够使癌细胞生长和存活的应激诱导型转录因子。在这里，我们发现，与其他癌症类型相比，原发性急性髓细胞白血病（AML）细胞表现出最高的eIF 4A 1转录水平。通过有效和特异性化合物rohinitib（RHT）抑制eIF 4A使这些细胞中的HSF 1失活，并对祖细胞和白血病起始细胞（尤其是具有FLT 3-内部串联重复（ITD）的那些）发挥显著的体外和体内抗白血病作用。除了其自身的抗白血病活性外，HSF 1的基因敲除还使FLT 3突变AML细胞对临床FLT 3抑制剂敏感，并且这种协同作用在携带ITD和酪氨酸激酶结构域突变的FLT 3双突变细胞中是保守的。一致地，RHT和FLT 3抑制剂的组合在原代FLT 3突变的AML细胞中具有高度协同作用。我们的研究结果为共同靶向eIF 4A和FLT 3以解决治疗FLT 3突变型AML的临床挑战提供了新的治疗原理。
Eukaryotic initiation factor 4A (eIF4A), the enzymatic core of the eIF4F complex essential for translation initiation, plays a key role in the oncogenic reprogramming of protein synthesis, and thus is a putative therapeutic target in cancer. As important component of its anticancer activity, inhibition of translation initiation can alleviate oncogenic activation of HSF1, a stress-inducible transcription factor that enables cancer cell growth and survival. Here, we show that primary acute myeloid leukemia (AML) cells exhibit the highest transcript levels of eIF4A1 compared to other cancer types. eIF4A inhibition by the potent and specific compound rohinitib (RHT) inactivated HSF1 in these cells, and exerted pronounced in vitro and in vivo anti-leukemia effects against progenitor and leukemia-initiating cells, especially those with FLT3-internal tandem duplication (ITD). In addition to its own anti-leukemic activity, genetic knockdown of HSF1 also sensitized FLT3-mutant AML cells to clinical FLT3 inhibitors, and this synergy was conserved in FLT3 double-mutant cells carrying both ITD and tyrosine kinase domain mutations. Consistently, the combination of RHT and FLT3 inhibitors was highly synergistic in primary FLT3-mutated AML cells. Our results provide a novel therapeutic rationale for co-targeting eIF4A and FLT3 to address the clinical challenge of treating FLT3-mutant AML.
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影响因子：
8.8
作者：
Descamps, G.;Gomez-Bougie, P.;Tamburini, J.;Green, A.;Bouscary, D.;Maiga, S.;Moreau, P.;Le Gouill, S.;Pellat-Deceunynck, C.;Amiot, M.
通讯作者：
Amiot, M.
影响因子：
3.7
作者：
Chou SD;Prince T;Gong J;Calderwood SK
通讯作者：
Calderwood SK
影响因子：
7.3
作者：
Ishizawa J;Kojima K;Chachad D;Ruvolo P;Ruvolo V;Jacamo RO;Borthakur G;Mu H;Zeng Z;Tabe Y;Allen JE;Wang Z;Ma W;Lee HC;Orlowski R;Sarbassov dos D;Lorenzi PL;Huang X;Neelapu SS;McDonnell T;Miranda RN;Wang M;Kantarjian H;Konopleva M;Davis RE;Andreeff M
通讯作者：
Andreeff M
影响因子：
4.5
作者：
Gupta, Sneha V.;Sass, Ellen J.;Lucas, David M.
通讯作者：
Lucas, David M.
影响因子：
4.5
作者：
Galicia-Vazquez, Gabriela;Cencic, Regina;Pelletier, Jerry
通讯作者：
Pelletier, Jerry