Oncotarget

Research Papers:

The PIM family of oncoproteins: small kinases with huge implications in myeloid leukemogenesis and as therapeutic targets

Kumar Saurabh, Michael T. Scherzer, Parag P. Shah, Alice S. Mims, William W. Lockwood, Andrew S. Kraft and Levi J. Beverly _

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Oncotarget. 2014; 5:8503-8514. https://doi.org/10.18632/oncotarget.2330

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Abstract

Kumar Saurabh1,*, Michael T. Scherzer1,4,*, Parag P. Shah1, Alice S. Mims5, William W. Lockwood6, Andrew S. Kraft5 and Levi J. Beverly1,2,3,4

1 James Graham Brown Cancer Center, University of Louisville, Louisville, KY

2 Department of Medicine, Division of Hematology and Oncology, University of Louisville School of Medicine, Louisville, KY

3 Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY

4 Department of Bioengineering, J.B Speed School of Engineering, University of Louisville, Louisville, KY

5 Hollings Cancer Center, Medical University of South Carolina, Charleston, SC

6 Integrative Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

* These authors contributed equally to this work

Correspondence:

Levi J. Beverly, email:

Keywords: PIM-1, PIM-2, PIM-3, MYC, leukemia

Received: July 08, 2014 Accepted: August 07, 2014 Published: August 08, 2014

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.


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