Pre-clinical evidence of PIM kinase inhibitor activity in BCR-ABL1 unmutated and mutated Philadelphia chromosome-positive (Ph+) leukemias
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Dany A. Curi1,2, Elspeth M. Beauchamp1,3,4, Gavin T. Blyth1,3, Ahmet Dirim Arslan1,3, Nicholas J. Donato5, Francis J. Giles1,3, Jessica K. Altman1,3,4, Leonidas C. Platanias1,3,4
1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
2Division of Hematology-Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA
3Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
4Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA
5Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, MI, USA
Leonidas C. Platanias, e-mail: email@example.com
Keywords: CML, PIM kinase, mTOR signaling, philadelphia chromosome-positive leukemia
Received: June 13, 2015 Accepted: August 26, 2015 Published: September 07, 2015
We investigated the efficacy of targeting the PIM kinase pathway in Philadelphia chromosome-positive (Ph+) leukemias. We provide evidence that inhibition of PIM, with the pan-PIM inhibitor SGI-1776, results in suppression of classic PIM effectors and also elements of the mTOR pathway, suggesting interplay between PIM and mTOR signals. Our data demonstrate that PIM inhibition enhances the effects of imatinib mesylate on Ph+ leukemia cells. We also found that PIM inhibition results in suppression of leukemic cell proliferation and induction of apoptosis of Ph+ leukemia cells, including those resistant to imatinib mesylate. Importantly, inhibition of PIM results in enhanced suppression of primary leukemic progenitors from patients with CML. Altogether these findings suggest that pharmacological PIM targeting may provide a unique therapeutic approach for the treatment of Ph+ leukemias.
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