@article{Bing Z. Carter_Po Yee Mak_Hong Mu_Xiangmeng Wang_Wenjing Tao_Duncan H. Mak_Elisha J. Dettman_Michael Cardone_Oleg Zernovak_Takahiko Seki_Michael Andreeff_2020, place={Pavia, Italy}, title={Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model}, volume={105}, url={https://haematologica.org/article/view/9383}, DOI={10.3324/haematol.2019.219261}, abstractNote={Although highly effective, BCR-ABL1 tyrosine kinase inhibitors do not target chronic myeloid leukemia (CML) stem cells. Most patients relapse upon tyrosine kinase inhibitor therapy cessation. We reported previously that combined BCR-ABL1 and BCL-2 inhibition synergistically targets CML stem/progenitor cells. p53 induces apoptosis mainly by modulating BCL-2 family proteins. Although infrequently mutated in CML, p53 is antagonized by MDM2, which is regulated by BCR-ABL1 signaling. We hypothesized that MDM2 inhibition could sensitize CML cells to tyrosine kinase inhibitors. Using an inducible transgenic Scl-tTa-<em>BCR-ABL1</em> murine CML model, we found, by RT-PCR and CyTOF proteomics increased p53 signaling in CML bone marrow (BM) cells compared with controls in CD45<sup>+</sup> and linage-SCA-1<sup>+</sup>C-KIT<sup>+</sup> populations. CML BM 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<sup>+</sup>C-KIT<sup>+</sup> cells and hematopoiesis, decreased leukemia burden, significantly prolonged the survival of mice engrafted with BM cells from Scl-tTa-<em>BCR-ABL1</em&gt; mice, and significantly decreased CML stem cell frequency in secondary transplantations. Our results suggest that CML stem/progenitor cells have increased p53 signaling and a propensity for apoptosis. Combined MDM2 and BCR-ABL1 inhibition targets CML stem/progenitor cells and has the potential to improve cure rates for CML.}, number={5}, journal={Haematologica}, author={Bing Z. Carter and Po Yee Mak and Hong Mu and Xiangmeng Wang and Wenjing Tao and Duncan H. Mak and Elisha J. Dettman and Michael Cardone and Oleg Zernovak and Takahiko Seki and Michael Andreeff}, year={2020}, month={May}, pages={1274-1284} }