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PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1)

Decker, Sarah and Finter, Johannes and Forde, Aaron James and Kissel, Sandra and Schwaller, Juerg and Mack, Thomas Sebastian and Kuhn, Anabel and Gray, Nathanael and Follo, Marie and Jumaa, Hassan and Burger, Meike and Zirlik, Katja and Pfeifer, Dietmar and Miduturu, Chandrasekhar V. and Eibel, Hermann and Veelken, Hendrik and Dierks, Christine. (2014) PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1). Molecular Cancer Therapeutics, 13 (5). pp. 1231-1245.

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Official URL: https://edoc.unibas.ch/62069/

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Abstract

Overexpression of the CXCR4 receptor is a hallmark of chronic lymphocytic leukemia (CLL) and is important for CLL cell survival, migration, and interaction with their protective microenvironment. In acute myelogenous leukemia (AML), PIM1 was shown to regulate the surface expression of the CXCR4 receptor. Here, we show that PIM (proviral integration site for Moloney murine leukemia virus) kinases 1-3 are overexpressed and that the CXCR4 receptor is hyperphosphorylated on Ser339 in CLL compared with normal lymphocytes. Furthermore, CXCR4 phosphorylation correlates with PIM1 protein expression and PIM1 transcript levels in CLL. PIM kinase inhibition with three different PIM kinase inhibitors induced apoptosis in CLL cells independent of the presence of protective stromal cells. In addition, PIM inhibition caused dephosphorylation of the CXCR4 receptor on Ser339, resulting in enhanced ligand-dependent CXCR4 internalization and reduced re-externalization after withdrawal of CXCL12. Furthermore, PIM inhibition in CLL cells blocked CXCR4 functions, such as migration toward CXCL12- or CXCL12-induced extracellular signal-regulated kinase (ERK) phosphorylation. In concordance, pretreatment of CLL cells with PIM kinase inhibitors strongly reduced homing of CLL cells toward the bone marrow and the spleen of Rag2(-/-)γc(-/-) mice in vivo. Interestingly, the knockdown of PIM kinases in CLL cells demonstrated diverging functions, with PIM1 regulating CXCR4 surface expression and PIM2 and PIM3 as important for the survival of CLL cells. Our results show that PIM kinase inhibitors are an effective therapeutic option for CLL, not only by impairing PIM2/3-mediated CLL cell survival, but also by blocking the PIM1/CXCR4-mediated interaction of CLL cells with their protective microenvironment.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Kindliche Leukämie (Schwaller)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Kindliche Leukämie (Schwaller)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Childhood Leukemia (Schwaller)
UniBasel Contributors:Schwaller, Jürg
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for Cancer Research
ISSN:1535-7163
e-ISSN:1538-8514
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Jun 2020 11:08
Deposited On:01 Jun 2020 11:08

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