Azacitidine resistance caused by LAMP2 deficiency: a therapeutic window for the use of autophagy inhibitors in MDS/AML patients?

Chaperone-mediated autophagy (CMA) is a selective form of autophagy that allows the elimination and recycling of cytosolic proteins endowed with a KFERQ-like motif into the lysosome. During this process, the proteins to be degraded are recognized by cellular chaperones such as HSC70 and presented to the CMA receptor LAMP2A, which then translocate them into lysosomes for degradation. In this punctum, we discuss the mechanisms underlying the response and resistance to Azacitidine (Aza) in MDS/AML cell lines and bone marrow CD34+ blasts from MDS/AML patients. We show that treatment of MDS/AML cell lines and bone marrow samples from MDS/AML patients with Aza triggers loss of LAMP2 expression leading to CMA defects. LAMP2 deficiency is responsible for CMA defects, Aza resistance and hypersensitivity to lysosome and autophagy inhibitors. Low levels of LAMP2 expression in CD34+ blasts from MDS/AML patients correlate with an absence of response to Aza and are associated to a pejorative overall survival. We propose that CD34+/LAMP2Low patients at diagnosis or who become CD34+/LAMP2Low during the course of treatment with Aza could receive an autophagy inhibitor available in the clinic.