title: Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser727.
abstract: 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 (Tyr705)-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.
authors.affiliation: 1] Institut Cochin, Inserm U1016, Paris, France [2] Service d'Hématologie-Immunologie, Hôpital Ambroise Paré, Boulogne-Billancourt, France [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [4] CNRS UMR8104, Paris, France [5] Université de Versailles St Quentin en Yvelines, Guyancourt, France.
authors.forename: C
authors.initials: C
authors.lastname: Capron
authors.affiliation: 1] Service d'Hématologie-Immunologie, Hôpital Ambroise Paré, Boulogne-Billancourt, France [2] Université de Versailles St Quentin en Yvelines, Guyancourt, France.
authors.forename: K
authors.initials: K
authors.lastname: Jondeau
authors.affiliation: 1] Institut Cochin, Inserm U1016, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] CNRS UMR8104, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Casetti
authors.affiliation: Service d'Hématologie-Immunologie, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
authors.forename: V
authors.initials: V
authors.lastname: Jalbert
authors.affiliation: Ecole Normale Supérieure de Lyon, Université de Lyon, UCB-Lyon1, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Costa
authors.forename: E
authors.initials: E
authors.lastname: Verhoeyen
authors.affiliation: 1] Ecole Normale Supérieure de Lyon, Université de Lyon, UCB-Lyon1, Lyon, France [2] INSERM U1065, Lyon, France.
authors.forename: E
authors.initials: E
authors.lastname: Verhoyen
authors.affiliation: 1] Institut Cochin, Inserm U1016, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] CNRS UMR8104, Paris, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Massé
authors.affiliation: Service d'Hématologie Clinique, Hôpital Saint Antoine and Université UPMC, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Coppo
authors.affiliation: Service d'Hématologie Biologique, Hôtel-Dieu-CHU, Nantes, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Béné
authors.affiliation: 1] Institut Cochin, Inserm U1016, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] CNRS UMR8104, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Bourdoncle
authors.affiliation: 1] Institut Cochin, Inserm U1016, Paris, France [2] Service d'Hématologie-Immunologie, Hôpital Ambroise Paré, Boulogne-Billancourt, France [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [4] CNRS UMR8104, Paris, France [5] Université de Versailles St Quentin en Yvelines, Guyancourt, France.
authors.forename: E
authors.initials: E
authors.lastname: Cramer-Bordé
authors.affiliation: 1] Institut Cochin, Inserm U1016, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] CNRS UMR8104, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Dusanter-Fourt
mesh_terms: D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002470:Cell Survival; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008928:Mitochondria / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050796:STAT3 Transcription Factor; D012694:Serine