p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells.

Trocoli, A; Bensadoun, P; Richard, E; Labrunie, G; Merhi, F; Schläfli, Anna; Brigger, Daniel; Souquere, S; Pierron, G; Pasquet, J-M; Soubeyran, P; Reiffers, J; Ségal-Bendirdjian, E; Tschan, Mario; Djavaheri-Mergny, M (2014). p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells. Cell death and differentiation, 21(12), pp. 1852-1861. Nature Publishing Group 10.1038/cdd.2014.102

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	?? DCD5A442C1CAE17DE0405C82790C4DE2 ?? 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.) 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Med. Onkologie / Hämatologie (Erw.)
Graduate School:	Graduate School for Cellular and Biomedical Sciences (GCB)
UniBE Contributor:	Bill, Anna Magdalena, Brigger, Daniel, Tschan, Mario Paul
ISSN:	1350-9047
Publisher:	Nature Publishing Group
Language:	English
Submitter:	Doris Haefelin
Date Deposited:	27 Feb 2015 12:19
Last Modified:	05 Dec 2022 14:41
Publisher DOI:	10.1038/cdd.2014.102
PubMed ID:	25034783
URI:	https://boris.unibe.ch/id/eprint/63833