Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset

Sathish K.R. Padi, Libia A. Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H. Song, Jon C. Aster, Xue Zhong Yu, Shikhar Mehrotra, Andrew Kraft

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors. Gene profiling using a publically available T-ALL dataset demonstrated overexpression of PIM1 in the majority of early T-cell precursor (ETP)-ALLs and a small subset of non-ETP ALL. While the PIM inhibitors blocked growth, they also stimulated ERK and STAT5 phosphorylation, demonstrating that activation of additional signaling pathways occurs with PIM inhibitor treatment. To block these pathways, Ponatinib, a broadly active tyrosine kinase inhibitor (TKI) used to treat chronic myelogenous leukemia, was added to this PIM-inhibitor regimen. The combination of Ponatinib with a PIM inhibitor resulted in synergistic T-ALL growth inhibition and marked apoptotic cell death. Treatment of mice engrafted with human T-ALL with these two agents significantly decreased the tumor burden and improved the survival of treated mice. This dual therapy has the potential to be developed as a novel approach to treat T-ALL with high PIM expression.

Original languageEnglish (US)
Pages (from-to)30199-30216
Number of pages18
JournalOncotarget
Volume8
Issue number18
DOIs
StatePublished - 2017

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Protein Kinases
T-Lymphoid Precursor Cells
Cell Line
Therapeutics
Phosphotransferases
Growth Inhibitors
Amyloid Precursor Protein Secretases
Protein Kinase Inhibitors
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Tumor Burden
Protein-Tyrosine Kinases
Cell Death
Phosphorylation
Drug Therapy
Mutation
Survival
Growth

Keywords

  • ETP-ALL
  • PIM kinase
  • Ponatinib
  • T-ALL
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology

Cite this

Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset. / Padi, Sathish K.R.; Luevano, Libia A.; An, Ningfei; Pandey, Ritu; Singh, Neha; Song, Jin H.; Aster, Jon C.; Yu, Xue Zhong; Mehrotra, Shikhar; Kraft, Andrew.

In: Oncotarget, Vol. 8, No. 18, 2017, p. 30199-30216.

Research output: Contribution to journalArticle

Padi, SKR, Luevano, LA, An, N, Pandey, R, Singh, N, Song, JH, Aster, JC, Yu, XZ, Mehrotra, S & Kraft, A 2017, 'Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset', Oncotarget, vol. 8, no. 18, pp. 30199-30216. https://doi.org/10.18632/oncotarget.16320
Padi, Sathish K.R. ; Luevano, Libia A. ; An, Ningfei ; Pandey, Ritu ; Singh, Neha ; Song, Jin H. ; Aster, Jon C. ; Yu, Xue Zhong ; Mehrotra, Shikhar ; Kraft, Andrew. / Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset. In: Oncotarget. 2017 ; Vol. 8, No. 18. pp. 30199-30216.
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