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In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment

The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the mo...

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Autores principales: Severin, Filippo, Frezzato, Federica, Visentin, Andrea, Martini, Veronica, Trimarco, Valentina, Carraro, Samuela, Tibaldi, Elena, Brunati, Anna Maria, Piazza, Francesco, Semenzato, Gianpietro, Facco, Monica, Trentin, Livio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966457/
https://www.ncbi.nlm.nih.gov/pubmed/31817171
http://dx.doi.org/10.3390/cancers11121939
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author Severin, Filippo
Frezzato, Federica
Visentin, Andrea
Martini, Veronica
Trimarco, Valentina
Carraro, Samuela
Tibaldi, Elena
Brunati, Anna Maria
Piazza, Francesco
Semenzato, Gianpietro
Facco, Monica
Trentin, Livio
author_facet Severin, Filippo
Frezzato, Federica
Visentin, Andrea
Martini, Veronica
Trimarco, Valentina
Carraro, Samuela
Tibaldi, Elena
Brunati, Anna Maria
Piazza, Francesco
Semenzato, Gianpietro
Facco, Monica
Trentin, Livio
author_sort Severin, Filippo
collection PubMed
description The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the modulation of JAK2/STAT3 pathway in CLL by BMSCs and its targeting with AG490 (JAK2 inhibitor) or Stattic (STAT3 inhibitor). B cells collected from controls and CLL patients, were treated with medium alone, ibrutinib, JAK/Signal Transducer and Activator of Transcription (STAT) inhibitors, or both drugs, in the presence of absence of BMSCs. JAK2/STAT3 axis was evaluated by western blotting, flow cytometry, and confocal microscopy. We demonstrated that STAT3 was phosphorylated in Tyr705 in the majority of CLL patients at basal condition, and increased following co-cultures with BMSCs or IL-6. Treatment with AG490, but not Stattic, caused STAT3 and Lyn dephosphorylation, through re-activation of SHP-1, and triggered CLL apoptosis even when leukemic cells were cultured on BMSC layers. Moreover, while BMSCs hamper ibrutinib activity, the combination of ibrutinib+JAK/STAT inhibitors increase ibrutinib-mediated leukemic cell death, bypassing the pro-survival stimuli derived from BMSCs. We herein provide evidence that JAK2/STAT3 signaling might play a key role in the regulation of CLL-BMSC interactions and its inhibition enhances ibrutinib, counteracting the bone marrow niche.
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spelling pubmed-69664572020-01-27 In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment Severin, Filippo Frezzato, Federica Visentin, Andrea Martini, Veronica Trimarco, Valentina Carraro, Samuela Tibaldi, Elena Brunati, Anna Maria Piazza, Francesco Semenzato, Gianpietro Facco, Monica Trentin, Livio Cancers (Basel) Article The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the modulation of JAK2/STAT3 pathway in CLL by BMSCs and its targeting with AG490 (JAK2 inhibitor) or Stattic (STAT3 inhibitor). B cells collected from controls and CLL patients, were treated with medium alone, ibrutinib, JAK/Signal Transducer and Activator of Transcription (STAT) inhibitors, or both drugs, in the presence of absence of BMSCs. JAK2/STAT3 axis was evaluated by western blotting, flow cytometry, and confocal microscopy. We demonstrated that STAT3 was phosphorylated in Tyr705 in the majority of CLL patients at basal condition, and increased following co-cultures with BMSCs or IL-6. Treatment with AG490, but not Stattic, caused STAT3 and Lyn dephosphorylation, through re-activation of SHP-1, and triggered CLL apoptosis even when leukemic cells were cultured on BMSC layers. Moreover, while BMSCs hamper ibrutinib activity, the combination of ibrutinib+JAK/STAT inhibitors increase ibrutinib-mediated leukemic cell death, bypassing the pro-survival stimuli derived from BMSCs. We herein provide evidence that JAK2/STAT3 signaling might play a key role in the regulation of CLL-BMSC interactions and its inhibition enhances ibrutinib, counteracting the bone marrow niche. MDPI 2019-12-04 /pmc/articles/PMC6966457/ /pubmed/31817171 http://dx.doi.org/10.3390/cancers11121939 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Severin, Filippo
Frezzato, Federica
Visentin, Andrea
Martini, Veronica
Trimarco, Valentina
Carraro, Samuela
Tibaldi, Elena
Brunati, Anna Maria
Piazza, Francesco
Semenzato, Gianpietro
Facco, Monica
Trentin, Livio
In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment
title In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment
title_full In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment
title_fullStr In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment
title_full_unstemmed In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment
title_short In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment
title_sort in chronic lymphocytic leukemia the jak2/stat3 pathway is constitutively activated and its inhibition leads to cll cell death unaffected by the protective bone marrow microenvironment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966457/
https://www.ncbi.nlm.nih.gov/pubmed/31817171
http://dx.doi.org/10.3390/cancers11121939
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