Inhibition of the proteasome and proteaphagy enhances apoptosis in FLT3‐ITD‐driven acute myeloid leukemia
Résumé
Acute myeloid leukaemia (AML) is a clonal disorder that affects hematopoietic stem cells or myeloid progenitors. One of the most common mutations that results in AML occurs in the gene encoding fms‐like tyrosine kinase 3 (FLT3). Previous studies demonstrated that AML cells expressing FLT3‐ITD are more sensitive to the proteasome inhibitor (PI) Bortezomib (Bz), than FLT3 wild‐type cells, and this cytotoxicity is mediated by autophagy. Here we show that proteasome inhibition with Bz results in modest but consistent proteaphagy in MOLM‐14 leukemic cells expressing the FLT3‐ITD mutation, but not in OCI‐AML3 leukemic cells with wild type FLT3. Chemical inhibition of autophagy with Bafilomycin A (BafA) simultaneously blocked proteaphagy and resulted in accumulation of the p62 autophagy receptor in Bz‐treated MOLM‐14 cells. The use of ubiquitin traps (TUBEs) revealed that ubiquitin plays an important role in proteasome‐autophagy crosstalk. The p62 inhibitor Verteporfin (VT) blocked proteaphagy and, importantly, resulted in accumulation of high molecular weight forms of p62 and FLT3‐ITD in Bz‐treated MOLM‐14 cells. Both autophagy inhibitors enhanced Bz‐induced apoptosis in FLT3‐ITD‐driven leukemic cells, underlining the therapeutic potential of these treatments.
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