TY - JOUR
T1 - p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells
AU - Trocoli, A.
AU - Bensadoun, P.
AU - Richard, E.
AU - Labrunie, G.
AU - Merhi, F.
AU - Schläfli, A. M.
AU - Brigger, D.
AU - Souquere, S.
AU - Pierron, G.
AU - Pasquet, J. M.
AU - Soubeyran, P.
AU - Reiffers, J.
AU - Ségal-Bendirdjian, E.
AU - Tschan, M. P.
AU - Djavaheri-Mergny, M.
N1 - Funding Information:
Acknowledgements. This work was supported by funds from the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Bordeaux, the Institut Bergonié, the ‘Conseil Regional d’Aquitaine’, the Ligue contre le Cancer Comité de la Gironde (to MDM), the ‘ INCa-DGOS-Inserm 6046 ‘ (to MDM), the Ligue contre le Cancer Comité Ile de France (to E S-B) and by grants from Swiss National Science Foundation (31003A_143739 to MPT), the Werner and Hedy Berger-Janser Foundation of Cancer Research (to MPT), and the Bern University Research Foundation (to MPT) AT is supported by a PhD fellowship from the Conseil Régional Aquitaine/INSERM (to M.D.M.). We gratefully acknowledge Dr. PJM Valk and Dr. B Löwenberg and the HOVON (Dutch-Belgian Hematology-Oncology) cooperative group for providing primary AML patient samples. We thank Prof. Richard Iggo for constructive advice and Pascal Correia (institut Bergonié, unité de biologie moléculaire, Bordeaux) for his technical support.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85027937046&partnerID=8YFLogxK
U2 - 10.1038/cdd.2014.102
DO - 10.1038/cdd.2014.102
M3 - Article
C2 - 25034783
AN - SCOPUS:85027937046
SN - 1350-9047
VL - 21
SP - 1852
EP - 1861
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 12
ER -