Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
20
08
2020
accepted:
21
05
2021
revised:
01
04
2021
pubmed:
16
6
2021
medline:
6
10
2021
entrez:
15
6
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34127794
doi: 10.1038/s41375-021-01308-z
pii: 10.1038/s41375-021-01308-z
pmc: PMC8764661
mid: NIHMS1769616
doi:
Substances chimiques
Antineoplastic Agents
0
Heat Shock Transcription Factors
0
Eukaryotic Initiation Factor-4A
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
2469-2481Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA175744
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118173
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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