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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, Jahrgang 13, Nr. 5, 05.2014, S. 1231-45.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Decker, S, Finter, J, Forde, AJ, Kissel, S, Schwaller, J, Mack, TS, Kuhn, A, Gray, N, Follo, M, Jumaa, H, Burger, M, Zirlik, K, Pfeifer, D, Miduturu, CV, Eibel, H, Veelken, H & Dierks, C 2014, 'PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1)', MOL CANCER THER, Jg. 13, Nr. 5, S. 1231-45. https://doi.org/10.1158/1535-7163.MCT-13-0575-T

APA

Decker, S., Finter, J., Forde, A. J., Kissel, S., Schwaller, J., Mack, T. S., Kuhn, A., Gray, N., Follo, M., Jumaa, H., Burger, M., Zirlik, K., Pfeifer, D., Miduturu, C. V., Eibel, H., Veelken, H., & Dierks, C. (2014). PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1). MOL CANCER THER, 13(5), 1231-45. https://doi.org/10.1158/1535-7163.MCT-13-0575-T

Vancouver

Decker S, Finter J, Forde AJ, Kissel S, Schwaller J, Mack TS et al. PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1). MOL CANCER THER. 2014 Mai;13(5):1231-45. https://doi.org/10.1158/1535-7163.MCT-13-0575-T

Bibtex

@article{5fb45e30d2524a878042d78527c8f699,
title = "PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1)",
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.",
keywords = "Animals, Apoptosis, Bone Marrow, Cell Line, Tumor, Cell Membrane, Cell Movement, DNA-Binding Proteins, Extracellular Signal-Regulated MAP Kinases, Gene Expression, Gene Knockdown Techniques, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, Mice, Knockout, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-pim-1, RNA, Small Interfering, Receptors, CXCR4, Spleen, Stromal Cells, Tumor Microenvironment, Journal Article, Research Support, Non-U.S. Gov't",
author = "Sarah Decker and Johannes Finter and Forde, {Aaron James} and Sandra Kissel and Juerg Schwaller and Mack, {Thomas Sebastian} and Anabel Kuhn and Nathanael Gray and Marie Follo and Hassan Jumaa and Meike Burger and Katja Zirlik and Dietmar Pfeifer and Miduturu, {Chandrasekhar V} and Hermann Eibel and Hendrik Veelken and Christine Dierks",
year = "2014",
month = may,
doi = "10.1158/1535-7163.MCT-13-0575-T",
language = "English",
volume = "13",
pages = "1231--45",
journal = "MOL CANCER THER",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

RIS

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 -