Pro-survival role of p62 during granulocytic differentiation of acute myeloid leukemia cells

International audiencep62 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

LEUKAEMIA INHIBITORY FACTOR EXPRESSION IS INHIBITED BY GLUCOCORTICOIDS THROUGH POST-TRANSCRIPTIONAL MECHANISMS

International audienceLeukaemia inhibitory factor (LIF) is a pleiotropic cytokine which is involved in the regulation of the immune response and haematopoiesis. The authors investigated the regulation of the expression of LIF by glucocorticosteroids (GC). Endothelial cells (EC) constitutively produce LIF and this production is enhanced by interleukin 1 (IL-1). GC were found to inhibit the basal production of LIF by EC and to suppress its IL-1-induced augmentation. Whether corticosteroids suppress LIF production by blocking transcription of LIF mRNA, or by blocking LIF synthesis at a post-transcriptional level was examined. Northern blot hybridization analysis demonstrated that GC act mainly by decreasing the LIF mRNA level. In the presence of translation inhibitors a superinduction of LIF mRNA was observed. Dexamethasone (DEX) at a concentration of 1 microM was responsible for a rapid increase in the degradation rate of LIF mRNA which resulted in reducing its level by more than 50% within 2 h, whereas the transcription rate of LIF gene was not significantly altered in these conditions. These results demonstrated that GC inhibit LIF mRNA expression mainly by increasing the turnover rate of the LIF mRNA. The early LIF mRNA destabilizing activity of GC was translation dependent as shown by experiments with protein translation inhibitors. The results indicate that corticosteroids are inhibitors of LIF expression and that this inhibition mainly occurs through post-transcriptional mechanisms

ATRA-induced upregulation of Beclin 1 prolongs the life span of differentiated acute promyelocytic leukemia cells

International audienceAcute promyelocytic leukemia (APL) results from a blockade of granulocyte differentiation at the promyelocytic stage. All-trans retinoic acid (ATRA) induces clinical remission in APL patients by enhancing the rapid differentiation of APL cells and the clearance of PML-RARα, APL's hallmark oncoprotein. In the present study, we demonstrated that both autophagy and Beclin 1, an autophagic protein, are upregulated during the course of ATRA-induced neutrophil/granulocyte differentiation of an APL-derived cell line named NB4 cells. This induction of autophagy is associated with downregulation of Bcl-2 and inhibition of mTOR activity. Small interfering RNA-mediated knockdown of BECN1 expression enhances apoptosis triggered by ATRA in NB4 cells but does not affect the differentiation process. These results provide evidence that the upregulation of Beclin 1 by ATRA constitutes an anti-apoptotic signal for maintaining the viability of mature APL cells, but has no crucial effect on the granulocytic differentiation. This finding may help to elucidate the mechanisms involved in ATRA resistance of APL patients, and in the ATRA syndrome caused by an accumulation of mature APL cells