Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 5488K) PDF+supp data (11052K) PPT slides of all figures Supplemental Material Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Grundler, R. Articles by Schwaller, J. PubMed PubMed Citation Articles by Grundler, R. Articles by Schwaller, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Substance via MeSH Social Bookmarking                            What's this?

¹ Department of Internal Medicine III, Technical University, Munich 81739, Germany
² Department of Biomedicine, University Hospital, Basel 4031, Switzerland
³ University of Oxford, Structural Genomics Consortium, Old Road Campus Research Centre, Oxford OX3 7DQ, England, UK
⁴ Centro M. Tettamanti-Clinica Pediatrica, Universita Milano-Bicocca, 20042 Monza, Italy
⁵ Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg 79111, Germany

CORRESPONDENCE Juerg Schwaller: J.Schwaller{at}unibas.ch OR Justus Duyster: Justus.Duyster{at}lrz.tum.de

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.

Abbreviations used: AML, acute myeloid leukemia; HSC, hematopoietic stem cell; mRNA, messenger RNA; PTK, protein tyrosine kinase; siRNA, small interfering RNA.

© 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/).

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Grundler, R., Brault, L., Gasser, C., Bullock, A. N., Dechow, T., Woetzel, S., Pogacic, V., Villa, A., Ehret, S., Berridge, G., Spoo, A., Dierks, C., Biondi, A., Knapp, S., Duyster, J., Schwaller, J. (2009). Dissection of PIM serine/threonine kinases in FLT3-ITD-induced leukemogenesis reveals PIM1 as regulator of CXCL12-CXCR4-mediated homing and migration. JCB 186: i7-i7 [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS