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.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10–15% of pediatric and 25% of adult ALL cases
The disease can be sub-classified into early T-cell precursor ALL (ETP-ALL), cortical, or mature T-ALL based on stage-specific differentiation markers, with ETPALLs being defined by the absence of CD4, CD8, and CD1a and frequent expression of one or more myeloid markers [1]
Because the PIM protein kinases have been shown to regulate the phosphorylation of 4E-BP1 [19], PRAS40 [20], and there is evidence that phosphoinositide-3 kinase (PI3K)–AKT and mammalian target of rapamycin pathways are activated in T-ALL [21, 22], we investigated whether PIM inhibitor treatment blocks the mTOR pathway in these leukemic cells
Summary
T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10–15% of pediatric and 25% of adult ALL cases. While intensive chemotherapy regimens result in remission in approximately 80% of pediatric and 45% of adult ALL patients, ETP-ALL is associated with a higher rate of relapse and induction failure, with a 10year overall survival of 19% as compared with 84% for all other T-ALLs [1,2,3]. Gain-offunction somatic mutations of the gene encoding NOTCH1 are found in 50% of T-ALL patients. Somatic mutations that disrupt the expression of FBXW7, the E3 ligase that mediates the degradation of NOTCH1, results in higher levels of NOTCH1 protein in 15% of T-ALL patients [4]. Patients with ETP-ALL have higher levels of minimal residual disease after induction therapy and require more intense and prolonged chemotherapy [3, 7]. Alternative treatment approaches are needed for this disease to obviate intensive chemotherapy and treat resistant disease
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