Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser727

被引:15
作者
Capron, C. [1 ,2 ,3 ,4 ,5 ]
Jondeau, K. [5 ]
Casetti, L. [1 ,2 ,3 ,4 ]
Jalbert, V.
Costa, C. [6 ]
Verhoyen, E. [6 ,7 ]
Masse, J. M. [1 ,2 ,3 ,4 ]
Coppo, P. [8 ,9 ]
Bene, M. C. [10 ]
Bourdoncle, P. [1 ,2 ,3 ,4 ]
Cramer-Borde, E. [1 ,2 ,3 ,4 ,5 ]
Dusanter-Fourt, I. [1 ,2 ,3 ,4 ]
机构
[1] INSERM, Inst Cochin, U1016, F-75014 Paris, France
[2] Hop Ambroise Pare, Serv Hematol Immunol, Boulogne Billancourt, France
[3] Univ Paris 05, Sorbonne Paris Cite, Paris, France
[4] CNRS, UMR8104, Paris, France
[5] Univ Versailles St Quentin Yvelines, Guyancourt, France
[6] Univ Lyon 1, Ecole Normale Super Lyon, F-69365 Lyon, France
[7] INSERM, U1065, F-69008 Lyon, France
[8] Hop St Antoine, Serv Hematol Clin, F-75571 Paris, France
[9] Univ Paris 06, Paris, France
[10] CHU Nantes, Hotel Dieu, Serv Hematol Biol, F-44035 Nantes 01, France
关键词
CHRONIC LYMPHOCYTIC-LEUKEMIA; SIGNAL TRANSDUCER; B-CELLS; ACTIVATES TRANSCRIPTION; SERINE; 727; STAT3; CLL; PROTEINS; SURVIVAL; DNA;
D O I
10.1038/cddis.2014.393
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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(727)) in the absence of detectable canonical tyrosine 705 (Tyr(705))-dependent activation in vivo. The Ser(727)-phosphorylated STAT3 molecule (pSTAT3Ser(727)) is localized to the mitochondria and associates with complex I of the respiratory chain. This pSer(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(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(727) overactivity is part of the antioxidant defense pathway of CLL B cells that regulates their viability. Mt pSTAT3Ser(727) appears to be a newly identified cell-protective signal involved in CLL cells survival. Targeting pSTAT3Ser(727) could be a promising new therapeutic approach.
引用
收藏
页码:e1451 / e1451
页数:11
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