Combined inhibition of MDM2 and Bcr-Abl tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model

Although highly effective, BCR-ABL1 tyrosine kinase inhibitors do not target chronic myeloid leukemia stem cells. Most patients relapse upon tyrosine kinase inhibitor therapy cessation. We reported previously that combined BCR-ABL1 and BCL-2 inhibition synergistically targets chronic myeloid leukemia stem/progenitor cells. p53 induces apoptosis mainly by modulating BCL-2 family proteins. Although infrequently mutated in chronic myeloid leukemia, p53 is antagonized by MDM2, which is regulated by BCR-ABL1 signaling. We hypothesized that MDM2 inhibition could sensitize chronic myeloid leukemia cells to tyrosine kinase inhibitors. Using an inducible transgenic Scl-tTa-BCR-ABL1 murine chronic myeloid leukemia model, we found, by RT-PCR and CyTOF proteomics increased p53 signaling in chronic myeloid leukemia bone marrow cells compared with controls in CD45+ and linage-SCA-1+C-KIT+ populations. Chronic myeloid leukemia bone marrow cells were more sensitive to exogenous BH3 peptides than controls. Combined inhibition of BCR-ABL1 with imatinib and MDM2 with DS-5272 increased NOXA level, markedly reduced leukemic linage-SCA-1+C-KIT+ cells and hematopoiesis, decreased leukemia burden, significantly prolonged the survival of mice engrafted with bone marrow cells from Scl-tTa-BCR-ABL1 mice, and significantly decreased chronic myeloid leukemia stem cell frequency in secondary transplantations. Our results suggest that chronic myeloid leukemia stem/progenitor cells have increased p53 signaling and a propensity for apoptosis. Combined MDM2 and BCR-ABL1 inhibition targets chronic myeloid leukemia stem/progenitor cells and has the potential to improve cure rates for chronic myeloid leukemia.