Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy. During CMA, the HSC70 chaperone carries target proteins endowed with a KFERQ-like motif to the lysosomal receptor LAMP2A, which then translocate them into lysosomes for degradation. In the present study, we scrutinized the mechanisms underlying the response and resistance to Azacytidine (Aza) in MDS/AML cell lines and bone marrow CD34+ blasts from MDS/AML patients. In engineered Aza-resistant MDS cell lines and some AML cell lines, we identified a profound defect in CMA linked to the absence of LAMP2A. LAMP2 deficiency was responsible for Aza resistance and hypersensitivity to lysosome and autophagy inhibitors. Accordingly, gain of function of LAMP2 in deficient cells or loss of function in LAMP2-expressing cells rendered them sensitive or resistant to Aza, respectively. A strict correlation was observed between the absence of LAMP2, resistance to Aza and sensitivity to lysosome inhibitors. Low levels of LAMP2 expression in CD34+ blasts from MDS/AML patients correlated with lack of sensitivity to Aza and were predictive of poor overall survival. We propose that CD34+/LAMP2Low patients at diagnosis or who become CD34+/LAMP2Low during the course of treatment with Aza might benefit from a lysosome inhibitor already used in the clinic.
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This work was supported by INSERM, INCA (PRTK-045, 2013–2015), the Fondation ARC pour la Recherche contre le Cancer (Equipe labellisée 2014–2017 and 2018–2020) and the Association Laurette Fugain (ALF 2016/08). This work was also funded by the French government (National Research Agency, ANR) through the “investissement for the future” LABEX SIGNALIFE program reference #ANR-11-LABEX-0028-01. AD is the recipient of a fellowship from the Fondation pour la Recherche Médicale. SB is the recipient of a fellowship from the Fondation ARC. MZ is the recipient of a fellowship from the LABEX SIGNALIFE program. AP is supported by the ATIP-AVENIR research grant and by the St Louis Association for leukemia research. Finally, this work was also supported by the Conseil General des Alpes Maritimes and the Conseil Regional PACA & Corse. The authors greatly acknowledge the C3M Imaging Core Facility part of MICA (Microscopy and Imaging Platform Côte d’Azur).
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This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1038/s41375-020-0969-8"
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Dubois, A., Furstoss, N., Calleja, A. et al. RETRACTED ARTICLE: LAMP2 expression dictates azacytidine response and prognosis in MDS/AML. Leukemia 33, 1501–1513 (2019). https://doi.org/10.1038/s41375-018-0336-1
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