title: p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells.
abstract: The p62/SQSTM1 adapter protein has an important role in the regulation of several key signaling pathways and helps transport ubiquitinated proteins to the autophagosomes and proteasome for degradation. Here, we investigate the regulation and roles of p62/SQSTM1 during acute myeloid leukemia (AML) cell maturation into granulocytes. Levels of p62/SQSTM1 mRNA and protein were both significantly increased during all-trans retinoic acid (ATRA)-induced differentiation of AML cells through a mechanism that depends on NF-κB activation. We show that this response constitutes a survival mechanism that prolongs the life span of mature AML cells and mitigates the effects of accumulation of aggregated proteins that occurs during granulocytic differentiation. Interestingly, ATRA-induced p62/SQSTM1 upregulation was impaired in maturation-resistant AML cells but was reactivated when differentiation was restored in these cells. Primary blast cells of AML patients and CD34(+) progenitors exhibited significantly lower p62/SQSTM1 mRNA levels than did mature granulocytes from healthy donors. Our results demonstrate that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and reveal a pro-survival function of the NF-κB/SQSTM1 signaling axis during granulocytic differentiation of AML cells. These findings may help our understanding of neutrophil/granulocyte development and will guide the development of novel therapeutic strategies for refractory and relapsed AML patients with previous exposure to ATRA.
authors.affiliation: 1] INSERM U916 VINCO, Institut Bergonié, 229, cours de l'Argonne 33076 Bordeaux Cedex, France [2] Université Bordeaux, 146 rue Léo-Saignat, F-33076 Bordeaux cedex, France.
authors.forename: A
authors.initials: A
authors.lastname: Trocoli
authors.affiliation: 1] INSERM U916 VINCO, Institut Bergonié, 229, cours de l'Argonne 33076 Bordeaux Cedex, France [2] Université Bordeaux, 146 rue Léo-Saignat, F-33076 Bordeaux cedex, France.
authors.forename: P
authors.initials: P
authors.lastname: Bensadoun
authors.affiliation: 1] INSERM U916 VINCO, Institut Bergonié, 229, cours de l'Argonne 33076 Bordeaux Cedex, France [2] Université Bordeaux, 146 rue Léo-Saignat, F-33076 Bordeaux cedex, France.
authors.forename: E
authors.initials: E
authors.lastname: Richard
authors.affiliation: 1] INSERM U916 VINCO, Institut Bergonié, 229, cours de l'Argonne 33076 Bordeaux Cedex, France [2] Université Bordeaux, 146 rue Léo-Saignat, F-33076 Bordeaux cedex, France.
authors.forename: G
authors.initials: G
authors.lastname: Labrunie
authors.affiliation: 1] INSERM U916 VINCO, Institut Bergonié, 229, cours de l'Argonne 33076 Bordeaux Cedex, France [2] Université Bordeaux, 146 rue Léo-Saignat, F-33076 Bordeaux cedex, France.
authors.forename: F
authors.initials: F
authors.lastname: Merhi
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: A M
authors.initials: AM
authors.lastname: Schläfli
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Brigger
authors.affiliation: UMR 8122, CNRS - IGR - Université Paris-XI, Villejuif, France.
authors.forename: S
authors.initials: S
authors.lastname: Souquere
authors.affiliation: UMR 8122, CNRS - IGR - Université Paris-XI, Villejuif, France.
authors.forename: G
authors.initials: G
authors.lastname: Pierron
authors.affiliation: INSERM U1035, Université Bordeaux, Bordeaux, France.
authors.forename: J-M
authors.initials: JM
authors.lastname: Pasquet
authors.affiliation: 1] INSERM U916 VINCO, Institut Bergonié, 229, cours de l'Argonne 33076 Bordeaux Cedex, France [2] Université Bordeaux, 146 rue Léo-Saignat, F-33076 Bordeaux cedex, France.
authors.forename: P
authors.initials: P
authors.lastname: Soubeyran
authors.affiliation: 1] INSERM U916 VINCO, Institut Bergonié, 229, cours de l'Argonne 33076 Bordeaux Cedex, France [2] Université Bordeaux, 146 rue Léo-Saignat, F-33076 Bordeaux cedex, France.
authors.forename: J
authors.initials: J
authors.lastname: Reiffers
authors.affiliation: INSERM UMR-S 1007, Cellular Homeostasis and Cancer, Université Paris Descartes, Sorbonne Paris Cité, 45 rue des Saints-Pères, 75006, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Ségal-Bendirdjian
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: M P
authors.initials: MP
authors.lastname: Tschan
authors.affiliation: 1] INSERM U916 VINCO, Institut Bergonié, 229, cours de l'Argonne 33076 Bordeaux Cedex, France [2] Université Bordeaux, 146 rue Léo-Saignat, F-33076 Bordeaux cedex, France.
authors.forename: M
authors.initials: M
authors.lastname: Djavaheri-Mergny
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071456:Sequestosome-1 Protein; D014212:Tretinoin / Q000494:pharmacology; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014212:Tretinoin