PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1)
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PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1). / Decker, Sarah; Finter, Johannes; Forde, Aaron James; Kissel, Sandra; Schwaller, Juerg; Mack, Thomas Sebastian; Kuhn, Anabel; Gray, Nathanael; Follo, Marie; Jumaa, Hassan; Burger, Meike; Zirlik, Katja; Pfeifer, Dietmar; Miduturu, Chandrasekhar V; Eibel, Hermann; Veelken, Hendrik; Dierks, Christine.
In: MOL CANCER THER, Vol. 13, No. 5, 05.2014, p. 1231-45.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1)
AU - Decker, Sarah
AU - Finter, Johannes
AU - Forde, Aaron James
AU - Kissel, Sandra
AU - Schwaller, Juerg
AU - Mack, Thomas Sebastian
AU - Kuhn, Anabel
AU - Gray, Nathanael
AU - Follo, Marie
AU - Jumaa, Hassan
AU - Burger, Meike
AU - Zirlik, Katja
AU - Pfeifer, Dietmar
AU - Miduturu, Chandrasekhar V
AU - Eibel, Hermann
AU - Veelken, Hendrik
AU - Dierks, Christine
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - Bone Marrow
KW - Cell Line, Tumor
KW - Cell Membrane
KW - Cell Movement
KW - DNA-Binding Proteins
KW - Extracellular Signal-Regulated MAP Kinases
KW - Gene Expression
KW - Gene Knockdown Techniques
KW - Humans
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - Mice
KW - Mice, Knockout
KW - Nuclear Proteins
KW - Phosphorylation
KW - Protein Binding
KW - Protein Kinase Inhibitors
KW - Protein-Serine-Threonine Kinases
KW - Proto-Oncogene Proteins
KW - Proto-Oncogene Proteins c-pim-1
KW - RNA, Small Interfering
KW - Receptors, CXCR4
KW - Spleen
KW - Stromal Cells
KW - Tumor Microenvironment
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1158/1535-7163.MCT-13-0575-T
DO - 10.1158/1535-7163.MCT-13-0575-T
M3 - SCORING: Journal article
C2 - 24659821
VL - 13
SP - 1231
EP - 1245
JO - MOL CANCER THER
JF - MOL CANCER THER
SN - 1535-7163
IS - 5
ER -