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Targeting PIM Kinases Impairs Survival of Hematopoietic Cells Transformed by Kinase Inhibitor–Sensitive and Kinase Inhibitor–Resistant Forms of Fms-Like Tyrosine Kinase 3 and BCR/ABL

¹ Department of Pathology, Geneva Medical School, Geneva, Switzerland; ² Department of Research, University Hospital Basel, Basel, Switzerland; ³ Division of Molecular Genetics, the Netherlands Cancer Institute, Amsterdam, the Netherlands; ⁴ Department of Internal Medicine III, Technical University of Munich, Munich, Germany; ⁵ Abramson Family Cancer Research Institute, Philadelphia; and the ⁶ Center for Human Genetics and Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium

Requests for reprints: Juerg Schwaller, Department of Research, Basel University Hospital, ZLF, Lab 318, Hebelstrasse 20, CH-4031 Basel, Switzerland. Phone: 41-61-265-3504; Fax: 41-22-37-24920; E-mail: J.Schwaller{at}unibas.ch.

Previous studies have shown that activation of the signal transducer and activator of transcription 5 (STAT5) plays an essential role in leukemogenesis mediated through constitutive activated protein tyrosine kinases (PTK). Because PIM-1 is a STAT5 target gene, we analyzed the role of the family of PIM serine/threonine kinases (PIM-1 to PIM-3) in PTK-mediated transformation of hematopoietic cells. Ba/F3 cells transformed to growth factor independence by various oncogenic PTKs (TEL/JAK2, TEL/TRKC, TEL/ABL, BCR/ABL, FLT3-ITD, and H4/PDGFßR) show abundant expression of PIM-1 and PIM-2. Suppression of PIM-1 activity had a negligible effect on transformation. In contrast, expression of kinase-dead PIM-2 mutant (PIM-2KD) led to a rapid decline of survival in Ba/F3 cells transformed by FLT3-ITD but not by other oncogenic PTKs tested. Coexpression of PIM-1KD and PIM-2KD abrogated growth factor–independent growth of Ba/F3 transformed by several PTKs, including BCR/ABL. Targeted down-regulation of PIM-2 by RNA interference (RNAi) selectively abrogated survival of Ba/F3 cells transformed by various Fms-like tyrosine kinase 3 (FLT3)–activating mutants [internal tandem duplication (ITD) and kinase domain] and attenuated growth of human cell lines containing FLT3 mutations. Interestingly, cells transformed by FLT3 and BCR/ABL mutations that confer resistance to small-molecule tyrosine kinase inhibitors were still sensitive to knockdown of PIM-2, or PIM-1 and PIM-2 by RNAi. Our observations indicate that combined inactivation of PIM-1 and PIM-2 interferes with oncogenic PTKs and suggest that PIMs are alternative therapeutic targets in PTK-mediated leukemia. Targeting the PIM kinase family could provide a new avenue to overcome resistance against small-molecule tyrosine kinase inhibitors. (Cancer Res 2006; 66(7): 3828-35)

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