PMID- 30607021
OWN - NLM
STAT- MEDLINE
DCOM- 20190906
LR  - 20210209
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 33
IP  - 6
DP  - 2019 Jun
TI  - LAMP2 expression dictates azacytidine response and prognosis in MDS/AML.
PG  - 1501-1513
LID - 10.1038/s41375-018-0336-1 [doi]
AB  - 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(+)/LAMP2(Low) patients 
      at diagnosis or who become CD34(+)/LAMP2(Low) during the course of treatment with 
      Aza might benefit from a lysosome inhibitor already used in the clinic.
FAU - Dubois, Alix
AU  - Dubois A
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
FAU - Furstoss, Nathan
AU  - Furstoss N
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
FAU - Calleja, Anne
AU  - Calleja A
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - CHU de Nice, Departement d'Hematologie Clinique, Nice, France.
FAU - Zerhouni, Marwa
AU  - Zerhouni M
AD  - Universite Cote d'Azur, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
FAU - Cluzeau, Thomas
AU  - Cluzeau T
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - CHU de Nice, Departement d'Hematologie Clinique, Nice, France.
FAU - Savy, Coline
AU  - Savy C
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
FAU - Marchetti, Sandrine
AU  - Marchetti S
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
FAU - Hamouda, Mohamed Amine
AU  - Hamouda MA
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
FAU - Boulakirba, Sonia
AU  - Boulakirba S
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
FAU - Orange, Francois
AU  - Orange F
AD  - Universite Cote d'Azur, Nice, France.
AD  - Centre Commun de Microscopie Appliquee, Nice, France.
FAU - Lacas-Gervais, Sandra
AU  - Lacas-Gervais S
AD  - Universite Cote d'Azur, Nice, France.
AD  - Centre Commun de Microscopie Appliquee, Nice, France.
FAU - Karsenti, Jean-Michel
AU  - Karsenti JM
AD  - CHU de Nice, Departement d'Hematologie Clinique, Nice, France.
FAU - Mounier, Nicolas
AU  - Mounier N
AD  - Universite Cote d'Azur, Nice, France.
AD  - CHU de Nice, Departement d'Hematologie Clinique, Nice, France.
FAU - Tamburini, Jerome
AU  - Tamburini J
AD  - Institut Cochin, CNRS, UMR 8104, INSERM U1016, Universite Paris Descartes, Paris, 
      France.
FAU - Puissant, Alexandre
AU  - Puissant A
AD  - Inserm U944, Institut Universitaire d'Hematologie, Hopital St Louis, Paris, 
      France.
FAU - Luciano, Frederic
AU  - Luciano F
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
FAU - Jacquel, Arnaud
AU  - Jacquel A
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
FAU - Auberger, Patrick
AU  - Auberger P
AD  - Universite Cote d'Azur, Nice, France.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France.
AD  - CHU de Nice, Departement d'Hematologie Clinique, Nice, France.
FAU - Robert, Guillaume
AU  - Robert G
AD  - Universite Cote d'Azur, Nice, France. robertg@unice.fr.
AD  - Inserm U1065, C3M, Team: Myeloid Malignancies and Multiple Myeloma, Nice, France. 
      robertg@unice.fr.
AD  - Equipe Labellisee par la Fondation ARC, Paris, France. robertg@unice.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Retracted Publication
DEP - 20190103
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (LAMP2 protein, human)
RN  - 0 (Lysosomal-Associated Membrane Protein 2)
RN  - M801H13NRU (Azacitidine)
SB  - IM
CIN - Autophagy. 2019 May;15(5):927-929. PMID: 30806567
RIN - Leukemia. 2020 Sep;34(9):2544. PMID: 32665699
MH  - Aged
MH  - Aged, 80 and over
MH  - Antimetabolites, Antineoplastic/*pharmacology
MH  - Apoptosis
MH  - Azacitidine/*pharmacology
MH  - Biomarkers, Tumor/genetics/*metabolism
MH  - Cell Proliferation
MH  - Female
MH  - Follow-Up Studies
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Humans
MH  - Leukemia, Myeloid, Acute/drug therapy/metabolism/*pathology
MH  - Lysosomal-Associated Membrane Protein 2/genetics/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Prognosis
MH  - Survival Rate
MH  - Tumor Cells, Cultured
EDAT- 2019/01/05 06:00
MHDA- 2019/09/07 06:00
CRDT- 2019/01/05 06:00
PHST- 2018/06/08 00:00 [received]
PHST- 2018/11/28 00:00 [accepted]
PHST- 2018/11/21 00:00 [revised]
PHST- 2019/01/05 06:00 [pubmed]
PHST- 2019/09/07 06:00 [medline]
PHST- 2019/01/05 06:00 [entrez]
AID - 10.1038/s41375-018-0336-1 [pii]
AID - 10.1038/s41375-018-0336-1 [doi]
PST - ppublish
SO  - Leukemia. 2019 Jun;33(6):1501-1513. doi: 10.1038/s41375-018-0336-1. Epub 2019 Jan 
      3.