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Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration
Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimula...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010703/ https://www.ncbi.nlm.nih.gov/pubmed/29665227 http://dx.doi.org/10.1111/jcmm.13632 |
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author | Białopiotrowicz, Emilia Górniak, Patryk Noyszewska‐Kania, Monika Puła, Bartosz Makuch‐Łasica, Hanna Nowak, Grażyna Bluszcz, Aleksandra Szydłowski, Maciej Jabłonska, Ewa Piechna, Karolina Sewastianik, Tomasz Polak, Anna Lech‐Marańda, Ewa Budziszewska, Bożena K. Wasylecka‐Juszczyńska, Maja Borg, Katarzyna Warzocha, Krzysztof Czardybon, Wojciech Gałęzowski, Michał Windak, Renata Brzózka, Krzysztof Juszczyński, Przemysław |
author_facet | Białopiotrowicz, Emilia Górniak, Patryk Noyszewska‐Kania, Monika Puła, Bartosz Makuch‐Łasica, Hanna Nowak, Grażyna Bluszcz, Aleksandra Szydłowski, Maciej Jabłonska, Ewa Piechna, Karolina Sewastianik, Tomasz Polak, Anna Lech‐Marańda, Ewa Budziszewska, Bożena K. Wasylecka‐Juszczyńska, Maja Borg, Katarzyna Warzocha, Krzysztof Czardybon, Wojciech Gałęzowski, Michał Windak, Renata Brzózka, Krzysztof Juszczyński, Przemysław |
author_sort | Białopiotrowicz, Emilia |
collection | PubMed |
description | Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimulation, and coculture with stromal cells increases PIMs expression in CLL cells, indicating microenvironment‐dependent PIMs regulation. PIM1 and PIM2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first‐line treatment. In primary CLL cells, inhibition of PIM kinases with a pan‐PIM inhibitor, SEL24‐B489, decreased PIM‐specific substrate phosphorylation and induced dose‐dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL24‐B489 was similar in TP53‐mutant and TP53 wild‐type cells. Finally, inhibition of PIM kinases decreased CXCR4‐mediated cell chemotaxis in two related mechanisms‐by decreasing CXCR4 phosphorylation and surface expression, and by limiting CXCR4‐triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL12‐triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment‐modulated PIM expression, their pro‐survival function and a role of PIMs in CXCR4‐induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease. |
format | Online Article Text |
id | pubmed-6010703 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60107032018-07-01 Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration Białopiotrowicz, Emilia Górniak, Patryk Noyszewska‐Kania, Monika Puła, Bartosz Makuch‐Łasica, Hanna Nowak, Grażyna Bluszcz, Aleksandra Szydłowski, Maciej Jabłonska, Ewa Piechna, Karolina Sewastianik, Tomasz Polak, Anna Lech‐Marańda, Ewa Budziszewska, Bożena K. Wasylecka‐Juszczyńska, Maja Borg, Katarzyna Warzocha, Krzysztof Czardybon, Wojciech Gałęzowski, Michał Windak, Renata Brzózka, Krzysztof Juszczyński, Przemysław J Cell Mol Med Original Articles Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimulation, and coculture with stromal cells increases PIMs expression in CLL cells, indicating microenvironment‐dependent PIMs regulation. PIM1 and PIM2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first‐line treatment. In primary CLL cells, inhibition of PIM kinases with a pan‐PIM inhibitor, SEL24‐B489, decreased PIM‐specific substrate phosphorylation and induced dose‐dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL24‐B489 was similar in TP53‐mutant and TP53 wild‐type cells. Finally, inhibition of PIM kinases decreased CXCR4‐mediated cell chemotaxis in two related mechanisms‐by decreasing CXCR4 phosphorylation and surface expression, and by limiting CXCR4‐triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL12‐triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment‐modulated PIM expression, their pro‐survival function and a role of PIMs in CXCR4‐induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease. John Wiley and Sons Inc. 2018-04-17 2018-07 /pmc/articles/PMC6010703/ /pubmed/29665227 http://dx.doi.org/10.1111/jcmm.13632 Text en © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Białopiotrowicz, Emilia Górniak, Patryk Noyszewska‐Kania, Monika Puła, Bartosz Makuch‐Łasica, Hanna Nowak, Grażyna Bluszcz, Aleksandra Szydłowski, Maciej Jabłonska, Ewa Piechna, Karolina Sewastianik, Tomasz Polak, Anna Lech‐Marańda, Ewa Budziszewska, Bożena K. Wasylecka‐Juszczyńska, Maja Borg, Katarzyna Warzocha, Krzysztof Czardybon, Wojciech Gałęzowski, Michał Windak, Renata Brzózka, Krzysztof Juszczyński, Przemysław Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration |
title | Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration |
title_full | Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration |
title_fullStr | Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration |
title_full_unstemmed | Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration |
title_short | Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration |
title_sort | microenvironment‐induced pim kinases promote cxcr4‐triggered mtor pathway required for chronic lymphocytic leukaemia cell migration |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010703/ https://www.ncbi.nlm.nih.gov/pubmed/29665227 http://dx.doi.org/10.1111/jcmm.13632 |
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