title: The PIM family of oncoproteins: small kinases with huge implications in myeloid leukemogenesis and as therapeutic targets.
abstract: PIM kinases are a family of serine/threonine kinases involved in cell survival and proliferation. There is significant structural similarity between the three PIM kinases (PIM1, PIM2 and PIM3) and only few amino acid differences. Although, several studies have specifically monitored the role of PIM1 in tumorigenesis, much less is known about PIM2 and PIM3. Therefore, in this study we have used in vitro cell culture models and in vivo bone marrow infection/transplantation to assess the comparative signaling and oncogenic potential of each of the three PIM kinases. All three PIM kinases were able to protect FL5.12 cells from IL3 withdrawal induced death. Interestingly, the downstream signaling cascades were indistinguishable between the three kinases. Transplantation of murine bone marrow co-expressing MYC and PIM1, PIM2 or PIM3 caused rapid and uniformly lethal myeloid leukemia. De-induction of MYC 18 days following transplantation significantly increased the survival of mice, even with continual expression of PIM kinases. Alternatively, mice treated at the pre-leukemic stage with a PIM kinase inhibitor increased the lifespan of the mice, even with continual expression of the MYC transgene. These data demonstrate the role of PIM kinases in driving myeloid leukemia, and as candidate molecules for therapy against human malignancies.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY. These authors contributed equally to this work.
authors.forename: Kumar
authors.initials: K
authors.lastname: Saurabh
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY. Department of Bioengineering, J.B Speed School of Engineering, University of Louisville, Louisville, KY. These authors contributed equally to this work.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Scherzer
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY.
authors.forename: Parag P
authors.initials: PP
authors.lastname: Shah
authors.affiliation: Hollings Cancer Center, Medical University of South Carolina, Charleston, SC.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Mims
authors.affiliation: Integrative Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.affiliation: Hollings Cancer Center, Medical University of South Carolina, Charleston, SC.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kraft
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY. Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY.
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D007377:Interleukin-3; C490587:PIM2 protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C496634:PIM1 protein, human; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1