Inhibition of the proteasome and proteaphagy enhances apoptosis in FLT3‐ITD‐driven acute myeloid leukemia

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 have demonstrated that AML cells expressing FLT3‐internal tandem duplication (ITD) are more sensitive to the proteasome inhibitor bortezomib (Bz) than FLT3 wild‐type cells, with this cytotoxicity being mediated by autophagy (Atg). 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 Atg with bafilomycin A simultaneously blocked proteaphagy and resulted in the accumulation of the p62 Atg receptor in Bz‐treated MOLM‐14 cells. The use of ubiquitin traps revealed that ubiquitin plays an important role in proteasome‐Atg cross‐talk. The p62 inhibitor verteporfin blocked proteaphagy and, importantly, resulted in accumulation of high molecular weight forms of p62 and FLT3‐ITD in Bz‐treated MOLM‐14 cells. Both Atg inhibitors enhanced Bz‐induced apoptosis in FLT3‐ITD‐driven leukemic cells, highlighting the therapeutic potential of these treatments.