Showing papers by "Mojgan Djavaheri-Mergny published in 2014"
TL;DR: It is demonstrated that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and 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.
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.
53 citations
TL;DR: It is reported that p62 is upregulated during all-trans retinoic acid (ATRA)-induced terminal differentiation of acute myeloid leukemia (AML) cells and this response reduces levels of ubiquitinated protein aggregates in mature cells and protects these cells against ATRA treatment.
Abstract: p62 regulates key signaling pathways including those that control cell death and autophagy. Recently, we reported that p62 is upregulated during all-trans retinoic acid (ATRA)-induced terminal differentiation of acute myeloid leukemia (AML) cells. This response reduces levels of ubiquitinated protein aggregates in mature cells and protects these cells against ATRA treatment. Thus, p62 confers a survival advantage to mature AML cells.
8 citations