Oncogenic FLT3-ITD supports autophagy via ATF4 in acute myeloid leukemia

In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) account for up to 25% of cases and are associated with a poor outcome. In order to better target this AML subtype, a comprehensive view of how FLT3-ITD impacts AML cell biology is r...

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Bibliographic Details
Published in:Oncogene 2018-02, Vol.37 (6), p.787-797
Main Authors: Heydt, Q, Larrue, C, Saland, E, Bertoli, S, Sarry, J-E, Besson, A, Manenti, S, Joffre, C, Mansat-De Mas, V
Format: Article
Language:English
Subjects:
Activating transcription factor 4
Acute myelocytic leukemia
Acute myeloid leukemia
Analysis
Autophagy
Autophagy (Cytology)
Care and treatment
Cell growth
Cell proliferation
Cellular biology
Development and progression
Gene expression
Genetic aspects
Health aspects
Kinases
Leukemia
Life Sciences
Medical innovations
Mutation
Myeloid leukemia
Oncogenes
Original
Phagocytosis
Protein-tyrosine kinase receptors
Xenografts
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Summary:In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) account for up to 25% of cases and are associated with a poor outcome. In order to better target this AML subtype, a comprehensive view of how FLT3-ITD impacts AML cell biology is required. Here, we found that FLT3-ITD expression increased basal autophagy in AML cells, and that both pharmacological and genetic inhibition of the receptor reduced autophagy in primary AML samples and cell lines. Conditional expression of shRNAs against key autophagy proteins demonstrated that autophagy is required for AML cell proliferation in vitro and for leukemic cells survival in a mouse model of xenograft. Importantly, autophagy inhibition also overcame FLT3 inhibitor resistance both in vitro and in vivo. The transcription factor ATF4 was identified as an essential actor of FLT3-ITD-induced autophagy. Cellular levels of ATF4 were highly dependent on FLT3-ITD activity, and downregulation of ATF4 inhibited autophagy-dependent AML cell proliferation and improved overall mouse survival similarly to autophagy inhibition. These results suggest that targeting autophagy or ATF4 in patients expressing FLT3 mutations may represent a novel promising and innovative therapeutic strategy for AML.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2017.376