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Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML

Abstract

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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Fig. 1: High level expression of eIF4A are observed in human primary leukemias.
Fig. 2: RHT inhibits growth and survival of AML cells especially cells with FLT3-ITD.
Fig. 3: eIF4A inactivation exerts in vivo anti-leukemia effects in FLT3-ITD AML.
Fig. 4: eIF4A inhibition diminishes engraftment potential of AML-initiating cells.
Fig. 5: Inhibition of HSF1 transcriptional activity via eIF4A potentiates FLT3 inhibitor sensitivity in FLT3-mutant AML cells.
Fig. 6: Combinatorial RHT and FLT3 inhibition induces synergistic apoptosis in FLT3-ITD mutant AML cells.
Fig. 7: Combinatorial RHT and FLT3 inhibition induces synergistic apoptosis in FLT3-ITD/TKD double-mutant cells.

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Acknowledgements

We thank Dr. Numsen Hail, Jr. for manuscript preparation, and Dr. Kapil N. Bhalla for providing cell lines. This research was partially supported by Paul and Mary Haas Chair in Genetics (to M.A.), the NCI (1R01CA175744 to L.W. and J.A.P., Jr.), and the NIGMS (R35GM118173 to J.A.P, Jr.). We also thank Research Fellowship Programs from The Uehara Memorial Foundation (to Y.N.) and Overseas Research and from Japan Society for the Promotion of Science for funding (to Y.N. and J.I.) Part of this research was performed in the Flow Cytometry & Cellular Imaging Core Facility, which is supported in part by the NIH through M. D. Anderson’s Cancer Center Support Grant CA016672.

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J.I., J.A.P., Jr., L.W., and M.A. conceived and designed the study. YN, J.I., R.Z., L.H., H.A., S.P., R.O.J., V.R.R. and D.C. performed experiments and acquired the data. Y.N., J.I., M.C.J.M., S.L., and R.E.D. analyzed and/or interpreted the data. Y.N., J.I., A.J., W.D., R.E.D., J.A.P., Jr., L.W., and M.A. wrote, reviewed and/or revised the manuscript.

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Nishida, Y., Zhao, R., Heese, L.E. et al. Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML. Leukemia 35, 2469–2481 (2021). https://doi.org/10.1038/s41375-021-01308-z

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