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Role of Bruton’s tyrosine kinase in B cells and malignancies

Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia...

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Autores principales: Pal Singh, Simar, Dammeijer, Floris, Hendriks, Rudi W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817726/
https://www.ncbi.nlm.nih.gov/pubmed/29455639
http://dx.doi.org/10.1186/s12943-018-0779-z
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author Pal Singh, Simar
Dammeijer, Floris
Hendriks, Rudi W.
author_facet Pal Singh, Simar
Dammeijer, Floris
Hendriks, Rudi W.
author_sort Pal Singh, Simar
collection PubMed
description Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies. In particular, the orally administered irreversible BTK inhibitor ibrutinib is associated with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL), including patients with high-risk genetic lesions. Because ibrutinib is generally well tolerated and shows durable single-agent efficacy, it was rapidly approved for first-line treatment of patients with CLL in 2016. To date, evidence is accumulating for efficacy of ibrutinib in various other B cell malignancies. BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is currently a considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors. Efficacy of BTK inhibition as a single agent therapy is strong, but resistance may develop, fueling the development of combination therapies that improve clinical responses. In this review, we discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy.
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spelling pubmed-58177262018-02-23 Role of Bruton’s tyrosine kinase in B cells and malignancies Pal Singh, Simar Dammeijer, Floris Hendriks, Rudi W. Mol Cancer Review Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies. In particular, the orally administered irreversible BTK inhibitor ibrutinib is associated with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL), including patients with high-risk genetic lesions. Because ibrutinib is generally well tolerated and shows durable single-agent efficacy, it was rapidly approved for first-line treatment of patients with CLL in 2016. To date, evidence is accumulating for efficacy of ibrutinib in various other B cell malignancies. BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is currently a considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors. Efficacy of BTK inhibition as a single agent therapy is strong, but resistance may develop, fueling the development of combination therapies that improve clinical responses. In this review, we discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy. BioMed Central 2018-02-19 /pmc/articles/PMC5817726/ /pubmed/29455639 http://dx.doi.org/10.1186/s12943-018-0779-z Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Review
Pal Singh, Simar
Dammeijer, Floris
Hendriks, Rudi W.
Role of Bruton’s tyrosine kinase in B cells and malignancies
title Role of Bruton’s tyrosine kinase in B cells and malignancies
title_full Role of Bruton’s tyrosine kinase in B cells and malignancies
title_fullStr Role of Bruton’s tyrosine kinase in B cells and malignancies
title_full_unstemmed Role of Bruton’s tyrosine kinase in B cells and malignancies
title_short Role of Bruton’s tyrosine kinase in B cells and malignancies
title_sort role of bruton’s tyrosine kinase in b cells and malignancies
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817726/
https://www.ncbi.nlm.nih.gov/pubmed/29455639
http://dx.doi.org/10.1186/s12943-018-0779-z
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