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Leukemia. 2019 Jan 3. doi: 10.1038/s41375-018-0336-1. [Epub ahead of print]

LAMP2 expression dictates azacytidine response and prognosis in MDS/AML.

Author information

1
Université Côte d'Azur, Nice, France.
2
Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
3
Equipe Labellisée par la Fondation ARC, Paris, France.
4
CHU de Nice, Département d'Hématologie Clinique, Nice, France.
5
Centre Commun de Microscopie Appliquée, Nice, France.
6
Institut Cochin, CNRS, UMR 8104, INSERM U1016, Université Paris Descartes, Paris, France.
7
Inserm U944, Institut Universitaire d'Hématologie, Hôpital St Louis, Paris, France.
8
Université Côte d'Azur, Nice, France. robertg@unice.fr.
9
Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France. robertg@unice.fr.
10
Equipe Labellisée par la Fondation ARC, Paris, France. robertg@unice.fr.

Abstract

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.

PMID:
30607021
DOI:
10.1038/s41375-018-0336-1

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