دورية أكاديمية
Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML
| العنوان: | Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML |
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| المؤلفون: | Nishida, Yuki, Zhao, Ran, Heese, Lauren E., Akiyama, Hiroki, Patel, Shreya, Jaeger, Alex M., Jacamo, Rodrigo O., Kojima, Kensuke, Ma, Man Chun John, Ruvolo, Vivian R., Chachad, Dhruv, Devine, William, Lindquist, Susan, Davis, R. Eric, Porco Jr, John A., Whitesell, Luke, Andreeff, Michael, Ishizawa, Jo |
| سنة النشر: | 2021 |
| المجموعة: | Boston University: OpenBU |
| جغرافية الموضوع: | England |
| الوصف: | 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. ; R01 CA175744 - NCI NIH HHS; R35 GM118173 - NIGMS NIH HHS; P30 CA016672 - NCI NIH HHS ; Published version ; Supporting documentation ; Accepted manuscript |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | p. 2469 - 2481 |
| اللغة: | English |
| تدمد: | 1476-5551 |
| العلاقة: | Leukemia; https://www.ncbi.nlm.nih.gov/pubmed/34127794Test; Y. Nishida, R. Zhao, L.E. Heese, H. Akiyama, S. Patel, A.M. Jaeger, R.O. Jacamo, K. Kojima, M.C.J. Ma, V.R. Ruvolo, D. Chachad, W. Devine, S. Lindquist, R.E. Davis, J.A. Porco, L. Whitesell, M. Andreeff, J. Ishizawa. 2021. "Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML." Leukemia, Volume 35, Issue 9, pp. 2469 - 2481. https://doi.org/10.1038/s41375-021-01308-zTest; https://hdl.handle.net/2144/44443Test; 635848 |
| DOI: | 10.1038/s41375-021-01308-z |
| الإتاحة: | https://doi.org/10.1038/s41375-021-01308-zTest https://hdl.handle.net/2144/44443Test https://www.ncbi.nlm.nih.gov/pubmed/34127794Test |
| رقم الانضمام: | edsbas.F1A3E6F9 |
| قاعدة البيانات: | BASE |
| تدمد: | 14765551 |
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| DOI: | 10.1038/s41375-021-01308-z |