Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser sub(727)

• Published in: Cell death & disease 2014-10, Vol.5, p.e1451-e1451
• Main Authors: Capron, C, Jondeau, K, Casetti, L, Jalbert, V, Costa, C, Verhoeyen, E, Masse, J M, Coppo, P, Bene, M C, Bourdoncle, P, Cramer-Borde, E, Dusanter-Fourt, I
• Format: Article
• Language: English
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.393

Chronic lymphoid leukemia (CLL) is characterized by the accumulation of functionally defective CD5-positive B lymphocytes. The clinical course of CLL is highly variable, ranging from a long-lasting indolent disease to an unpredictable and rapidly progressing leukemia requiring treatment. It is thus important to identify novel factors that reflect disease progression or contribute to its assessment. Here, we report on a novel STAT3-mediated pathway that characterizes CLL B cells-extended viability and oxidative stress control. We observed that leukemic but not normal B cells from CLL patients exhibit constitutive activation of an atypical form of the STAT3 signaling factor, phosphorylated on serine 727 (Ser sub(727)) in the absence of detectable canonical tyrosine 705 (Tyr sub(705))-dependent activation in vivo. The Ser sub(727)-phosphorylated STAT3 molecule (pSTAT3Ser sub(727)) is localized to the mitochondria and associates with complex I of the respiratory chain. This pSer sub(727) modification is further controlled by glutathione-dependent antioxidant pathway(s) that mediate stromal protection of the leukemic B cells and regulate their viability. Importantly, pSTAT3Ser sub(727), but neither Tyr705-phosphorylated STAT3 nor total STAT3, levels correlate with prolonged in vivo CLL B cells survival. Furthermore, STAT3 activity contributes to the resistance to apoptosis of CLL, but not normal B cells, in vitro. These data reveal that mitochondrial (Mt) pSTAT3Ser sub(727) overactivity is part of the antioxidant defense pathway of CLL B cells that regulates their viability. Mt pSTAT3Ser sub(727) appears to be a newly identified cell-protective signal involved in CLL cells survival. Targeting pSTAT3Ser sub(727) could be a promising new therapeutic approach.