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.
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/PDGFbetaR) 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.
Department of Pathology, Geneva Medical School, Geneva, Switzerland.
Myriam
M
Adam
Vanda
V
Pogacic
Marina
M
Bendit
Richard
R
Chappuis
Martijn C
MC
Nawijn
Justus
J
Duyster
Casey J
CJ
Fox
Craig B
CB
Thompson
Jan
J
Cools
Juerg
J
Schwaller
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl; D018014:Gene Transfer Techniques; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000473:pathology; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim