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

Autor: Nishida Y; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Zhao R; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Heese LE; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Akiyama H; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Patel S; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jaeger AM; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Jacamo RO; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kojima K; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Hematology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan., Ma MCJ; Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ruvolo VR; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Chachad D; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Devine W; Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA., Lindquist S; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Davis RE; Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Porco JA Jr; Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA., Whitesell L; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Andreeff M; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mandreef@mdanderson.org., Ishizawa J; Department of Leukemia, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jishizawa@mdanderson.org.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2021 Sep; Vol. 35 (9), pp. 2469-2481. Date of Electronic Publication: 2021 Jun 14.
DOI: 10.1038/s41375-021-01308-z
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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