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Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration

FLT3-ITD–mediated leukemogenesis is associated with increased expression of oncogenic PIM serine/threonine kinases. To dissect their role in FLT3-ITD–mediated transformation, we performed bone marrow reconstitution assays. Unexpectedly, FLT3-ITD cells deficient for PIM1 failed to reconstitute lethal...

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Autores principales: Grundler, Rebekka, Brault, Laurent, Gasser, Christelle, Bullock, Alex N., Dechow, Tobias, Woetzel, Sabine, Pogacic, Vanda, Villa, Antonello, Ehret, Sabine, Berridge, Georgina, Spoo, Anke, Dierks, Christine, Biondi, Andrea, Knapp, Stefan, Duyster, Justus, Schwaller, Juerg
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737164/
https://www.ncbi.nlm.nih.gov/pubmed/19687226
http://dx.doi.org/10.1084/jem.20082074
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author Grundler, Rebekka
Brault, Laurent
Gasser, Christelle
Bullock, Alex N.
Dechow, Tobias
Woetzel, Sabine
Pogacic, Vanda
Villa, Antonello
Ehret, Sabine
Berridge, Georgina
Spoo, Anke
Dierks, Christine
Biondi, Andrea
Knapp, Stefan
Duyster, Justus
Schwaller, Juerg
author_facet Grundler, Rebekka
Brault, Laurent
Gasser, Christelle
Bullock, Alex N.
Dechow, Tobias
Woetzel, Sabine
Pogacic, Vanda
Villa, Antonello
Ehret, Sabine
Berridge, Georgina
Spoo, Anke
Dierks, Christine
Biondi, Andrea
Knapp, Stefan
Duyster, Justus
Schwaller, Juerg
author_sort Grundler, Rebekka
collection PubMed
description FLT3-ITD–mediated leukemogenesis is associated with increased expression of oncogenic PIM serine/threonine kinases. To dissect their role in FLT3-ITD–mediated transformation, we performed bone marrow reconstitution assays. Unexpectedly, FLT3-ITD cells deficient for PIM1 failed to reconstitute lethally irradiated recipients, whereas lack of PIM2 induction did not interfere with FLT3-ITD–induced disease. PIM1-deficient bone marrow showed defects in homing and migration and displayed decreased surface CXCR4 expression and impaired CXCL12–CXCR4 signaling. Through small interfering RNA–mediated knockdown, chemical inhibition, expression of a dominant-negative mutant, and/or reexpression in knockout cells, we found PIM1 activity to be essential for proper CXCR4 surface expression and migration of cells toward a CXCL12 gradient. Purified PIM1 led to the phosphorylation of serine 339 in the CXCR4 intracellular domain in vitro, a site known to be essential for normal receptor recycling. In primary leukemic blasts, high levels of surface CXCR4 were associated with increased PIM1 expression, and this could be significantly reduced by a small molecule PIM inhibitor in some patients. Our data suggest that PIM1 activity is important for homing and migration of hematopoietic cells through modification of CXCR4. Because CXCR4 also regulates homing and maintenance of cancer stem cells, PIM1 inhibitors may exert their antitumor effects in part by interfering with interactions with the microenvironment.
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spelling pubmed-27371642010-02-28 Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration Grundler, Rebekka Brault, Laurent Gasser, Christelle Bullock, Alex N. Dechow, Tobias Woetzel, Sabine Pogacic, Vanda Villa, Antonello Ehret, Sabine Berridge, Georgina Spoo, Anke Dierks, Christine Biondi, Andrea Knapp, Stefan Duyster, Justus Schwaller, Juerg J Exp Med Article FLT3-ITD–mediated leukemogenesis is associated with increased expression of oncogenic PIM serine/threonine kinases. To dissect their role in FLT3-ITD–mediated transformation, we performed bone marrow reconstitution assays. Unexpectedly, FLT3-ITD cells deficient for PIM1 failed to reconstitute lethally irradiated recipients, whereas lack of PIM2 induction did not interfere with FLT3-ITD–induced disease. PIM1-deficient bone marrow showed defects in homing and migration and displayed decreased surface CXCR4 expression and impaired CXCL12–CXCR4 signaling. Through small interfering RNA–mediated knockdown, chemical inhibition, expression of a dominant-negative mutant, and/or reexpression in knockout cells, we found PIM1 activity to be essential for proper CXCR4 surface expression and migration of cells toward a CXCL12 gradient. Purified PIM1 led to the phosphorylation of serine 339 in the CXCR4 intracellular domain in vitro, a site known to be essential for normal receptor recycling. In primary leukemic blasts, high levels of surface CXCR4 were associated with increased PIM1 expression, and this could be significantly reduced by a small molecule PIM inhibitor in some patients. Our data suggest that PIM1 activity is important for homing and migration of hematopoietic cells through modification of CXCR4. Because CXCR4 also regulates homing and maintenance of cancer stem cells, PIM1 inhibitors may exert their antitumor effects in part by interfering with interactions with the microenvironment. The Rockefeller University Press 2009-08-31 /pmc/articles/PMC2737164/ /pubmed/19687226 http://dx.doi.org/10.1084/jem.20082074 Text en © 2009 Grundler et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Grundler, Rebekka
Brault, Laurent
Gasser, Christelle
Bullock, Alex N.
Dechow, Tobias
Woetzel, Sabine
Pogacic, Vanda
Villa, Antonello
Ehret, Sabine
Berridge, Georgina
Spoo, Anke
Dierks, Christine
Biondi, Andrea
Knapp, Stefan
Duyster, Justus
Schwaller, Juerg
Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration
title Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration
title_full Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration
title_fullStr Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration
title_full_unstemmed Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration
title_short Dissection of PIM serine/threonine kinases in FLT3-ITD–induced leukemogenesis reveals PIM1 as regulator of CXCL12–CXCR4-mediated homing and migration
title_sort dissection of pim serine/threonine kinases in flt3-itd–induced leukemogenesis reveals pim1 as regulator of cxcl12–cxcr4-mediated homing and migration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737164/
https://www.ncbi.nlm.nih.gov/pubmed/19687226
http://dx.doi.org/10.1084/jem.20082074
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