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Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser(727)
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237234/ https://www.ncbi.nlm.nih.gov/pubmed/25299776 http://dx.doi.org/10.1038/cddis.2014.393 |
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author | Capron, C Jondeau, K Casetti, L Jalbert, V Costa, C Verhoyen, E Massé, J M Coppo, P Béné, M C Bourdoncle, P Cramer-Bordé, E Dusanter-Fourt, I |
author_facet | Capron, C Jondeau, K Casetti, L Jalbert, V Costa, C Verhoyen, E Massé, J M Coppo, P Béné, M C Bourdoncle, P Cramer-Bordé, E Dusanter-Fourt, I |
author_sort | Capron, C |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4237234 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-42372342014-11-26 Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser(727) Capron, C Jondeau, K Casetti, L Jalbert, V Costa, C Verhoyen, E Massé, J M Coppo, P Béné, M C Bourdoncle, P Cramer-Bordé, E Dusanter-Fourt, I Cell Death Dis Original Article 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. Nature Publishing Group 2014-10 2014-10-09 /pmc/articles/PMC4237234/ /pubmed/25299776 http://dx.doi.org/10.1038/cddis.2014.393 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0 |
spellingShingle | Original Article Capron, C Jondeau, K Casetti, L Jalbert, V Costa, C Verhoyen, E Massé, J M Coppo, P Béné, M C Bourdoncle, P Cramer-Bordé, E Dusanter-Fourt, I Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser(727) |
title | Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of
mitochondrial phosphoSTAT3Ser(727) |
title_full | Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of
mitochondrial phosphoSTAT3Ser(727) |
title_fullStr | Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of
mitochondrial phosphoSTAT3Ser(727) |
title_full_unstemmed | Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of
mitochondrial phosphoSTAT3Ser(727) |
title_short | Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of
mitochondrial phosphoSTAT3Ser(727) |
title_sort | viability and stress protection of chronic lymphoid leukemia cells involves overactivation of
mitochondrial phosphostat3ser(727) |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237234/ https://www.ncbi.nlm.nih.gov/pubmed/25299776 http://dx.doi.org/10.1038/cddis.2014.393 |
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