Dissection of PIM serine/threonine kinases in FLT3-ITD-induced leukemogenesis reveals PIM1 as regulator of CXCL12-CXCR4-mediated homing and migration
| Autor: | Laurent Brault, Rebekka Grundler, Vanda Pogacic, Juerg Schwaller, Justus Duyster, G. Berridge, Christelle Gasser, Antonello Villa, Christine Dierks, Stefan Knapp, Tobias Dechow, Sabine Woetzel, Anke Spoo, Andrea Biondi, Alex N. Bullock, Sabine Ehret |
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| Přispěvatelé: | Grundler, R, Brault, L, Gasser, C, Bullock, A, Dechow, T, Woetzel, S, Pogacic, V, Villa, A, Ehret, S, Berridge, G, Spoo, A, Dierks, C, Biondi, A, Knapp, S, Duyster, J, Schwaller, J |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Receptor recycling
Receptors CXCR4 DNA Primer Immunology Immunoblotting PIM1 Bone Marrow Cells Biology Jurkat cells Article Immunophenotyping 03 medical and health sciences Mice Jurkat Cells 0302 clinical medicine Proto-Oncogene Proteins c-pim-1 Cancer stem cell Cell Movement Immunology and Allergy Animals Humans Phosphorylation DNA Primers 030304 developmental biology Mice Knockout 0303 health sciences Protein-Serine-Threonine Kinases Animal Reverse Transcriptase Polymerase Chain Reaction Cell Biology Flow Cytometry Chemokine CXCL12 3. Good health Haematopoiesis Leukemia Myeloid Acute Cell Transformation Neoplastic fms-Like Tyrosine Kinase 3 030220 oncology & carcinogenesis Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Cancer research Bone Marrow Cell RNA Interference Homing (hematopoietic) 030215 immunology Human |
| Zdroj: | The Journal of Experimental Medicine |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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