Microenvironment‐induced PIM kinases promote CXCR4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration |
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| Authors: | Emilia Białopiotrowicz Patryk Górniak Monika Noyszewska‐Kania Bartosz Puła Hanna Makuch‐Łasica Grażyna Nowak Aleksandra Bluszcz Maciej Szydłowski Ewa Jabłonska Karolina Piechna Tomasz Sewastianik Anna Polak Ewa Lech‐Marańda Bożena K. Budziszewska Maja Wasylecka‐Juszczyńska Katarzyna Borg Krzysztof Warzocha Wojciech Czardybon Michał Gałęzowski Renata Windak Krzysztof Brzózka Przemysław Juszczyński |
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| Affiliation: | 1. Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;2. Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;3. Department of Diagnostic Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;4. Department of Hematology and Transfusion Medicine, Centre of Postgraduate Medical Education, Warsaw, Poland;5. Selvita S.A., Cracow, Poland |
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| Abstract: | 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. |
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| Keywords: | chronic lymphocytic leukaemia CXCR4 mTOR PIM kinase |
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