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Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is characterized by an aberrant cytokine network that can support tumor growth by triggering janus kinase (JAK)/STAT pathways. Targeting cytokine-signaling should then be a rational therapeutic strategy but the JAK inhibitor ruxolitinib failed to cont...

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Autores principales: Spaner, David E., Luo, Tina YuXuan, Wang, Guizhi, Schreiber, Gideon, Harari, Daniel, Shi, Yonghong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10126367/
https://www.ncbi.nlm.nih.gov/pubmed/37114129
http://dx.doi.org/10.3389/fonc.2023.1043694
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author Spaner, David E.
Luo, Tina YuXuan
Wang, Guizhi
Schreiber, Gideon
Harari, Daniel
Shi, Yonghong
author_facet Spaner, David E.
Luo, Tina YuXuan
Wang, Guizhi
Schreiber, Gideon
Harari, Daniel
Shi, Yonghong
author_sort Spaner, David E.
collection PubMed
description INTRODUCTION: Chronic lymphocytic leukemia (CLL) is characterized by an aberrant cytokine network that can support tumor growth by triggering janus kinase (JAK)/STAT pathways. Targeting cytokine-signaling should then be a rational therapeutic strategy but the JAK inhibitor ruxolitinib failed to control and seemingly accelerated the disease in clinical trials. METHODS: The effect of ruxolitinib on primary human CLL cells was studied in vitro and in vivo. RESULTS: Ruxolitinib increased phosphorylation of IRAK4, an important toll-like receptor (TLR)- signaling intermediate, in circulating CLL cells in vitro. It also enhanced p38 and NFKB1 phosphorylation while lowering STAT3 phosphorylation in CLL cells activated with TLR-7/8 agonists and IL-2. Among the cytokines made by activated CLL cells, high levels of IL-10 contributed strongly to STAT3 phosphorylation and inhibited TLR7 activity. Ruxolitinib limited TLR-mediated IL10 transcription and markedly reduced IL-10 production in vitro. It also decreased blood levels of IL-10 while increasing TNFα along with phospho-p38 expression and gene sets associated with TLR-activation in CLL cells in vivo. The bruton's tyrosine kinase inhibitor ibrutinib decreased IL-10 production in vitro but, in contrast to ruxolitinib, blocked initial IL10 transcription induced by TLR-signaling in vitro, decreased TNFα production, and deactivates CLL cells in vivo. DISCUSSION: These findings suggest the possible benefits of inhibiting growth factors with JAK inhibitors in CLL are outweighed by negative effects on potential tumor suppressors such as IL-10 that allow unrestrained activation of NFκB by drivers such as TLRs. Specific inhibition of growth-promoting cytokines with blocking antibodies or infusing suppressive cytokines like IL-10 might be better strategies to manipulate cytokines in CLL.
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spelling pubmed-101263672023-04-26 Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo Spaner, David E. Luo, Tina YuXuan Wang, Guizhi Schreiber, Gideon Harari, Daniel Shi, Yonghong Front Oncol Oncology INTRODUCTION: Chronic lymphocytic leukemia (CLL) is characterized by an aberrant cytokine network that can support tumor growth by triggering janus kinase (JAK)/STAT pathways. Targeting cytokine-signaling should then be a rational therapeutic strategy but the JAK inhibitor ruxolitinib failed to control and seemingly accelerated the disease in clinical trials. METHODS: The effect of ruxolitinib on primary human CLL cells was studied in vitro and in vivo. RESULTS: Ruxolitinib increased phosphorylation of IRAK4, an important toll-like receptor (TLR)- signaling intermediate, in circulating CLL cells in vitro. It also enhanced p38 and NFKB1 phosphorylation while lowering STAT3 phosphorylation in CLL cells activated with TLR-7/8 agonists and IL-2. Among the cytokines made by activated CLL cells, high levels of IL-10 contributed strongly to STAT3 phosphorylation and inhibited TLR7 activity. Ruxolitinib limited TLR-mediated IL10 transcription and markedly reduced IL-10 production in vitro. It also decreased blood levels of IL-10 while increasing TNFα along with phospho-p38 expression and gene sets associated with TLR-activation in CLL cells in vivo. The bruton's tyrosine kinase inhibitor ibrutinib decreased IL-10 production in vitro but, in contrast to ruxolitinib, blocked initial IL10 transcription induced by TLR-signaling in vitro, decreased TNFα production, and deactivates CLL cells in vivo. DISCUSSION: These findings suggest the possible benefits of inhibiting growth factors with JAK inhibitors in CLL are outweighed by negative effects on potential tumor suppressors such as IL-10 that allow unrestrained activation of NFκB by drivers such as TLRs. Specific inhibition of growth-promoting cytokines with blocking antibodies or infusing suppressive cytokines like IL-10 might be better strategies to manipulate cytokines in CLL. Frontiers Media S.A. 2023-04-11 /pmc/articles/PMC10126367/ /pubmed/37114129 http://dx.doi.org/10.3389/fonc.2023.1043694 Text en Copyright © 2023 Spaner, Luo, Wang, Schreiber, Harari and Shi https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Spaner, David E.
Luo, Tina YuXuan
Wang, Guizhi
Schreiber, Gideon
Harari, Daniel
Shi, Yonghong
Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo
title Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo
title_full Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo
title_fullStr Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo
title_full_unstemmed Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo
title_short Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo
title_sort paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10126367/
https://www.ncbi.nlm.nih.gov/pubmed/37114129
http://dx.doi.org/10.3389/fonc.2023.1043694
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