Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model
Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model
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DOI：
10.3324/haematol.2019.219261
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发表时间：
2020-05-01
期刊：
影响因子：
10.1
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
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作者：
Carter, Bing Z.;Mak, Po Yee;Andreeff, Michael
尽管BCR-ABL 1酪氨酸激酶抑制剂非常有效，但它并不靶向慢性粒细胞白血病（CML）干细胞。大多数患者在酪氨酸激酶抑制剂治疗停止后消失。我们以前报道过BCR-ABL 1和BCL-2联合抑制协同靶向CML干/祖细胞。p53主要通过调节BCL-2家族蛋白诱导细胞凋亡。尽管p53在CML中很少突变，但它被MDM 2拮抗，而MDM 2是由BCR-ABL 1信号转导调节的。我们假设MDM 2抑制可以使CML细胞对酪氨酸激酶抑制剂敏感。使用可诱导的转基因Sd-tTa-BCR-ABL 1小鼠CML模型，我们发现，通过RT-PCR和CyTOF蛋白质组学，与对照组相比，CML骨髓（BM）细胞中的CD 45中的p53信号增加。和家系-SCA-1（+）C-KIT+群体。CML BM细胞对外源性BH 3肽比对照更敏感。伊马替尼联合抑制BCR-ABL 1和DS-5272联合抑制MDM 2可增加NOXA水平，显著减少白血病谱系-SCA-1+C-KTP细胞和造血，降低白血病负荷，显著延长移植Sd-tTa-BCR-ABL 1小鼠BM细胞的小鼠的生存期，并显著降低二次移植中的CML干细胞频率。我们的研究结果表明，CML干/祖细胞有增加的p53信号和凋亡的倾向。MDM 2和BCR-ABL 1联合抑制靶向CML干/祖细胞，并有可能提高CML的治愈率。
Although highly effective, BCR-ABL1 tyrosine kinase inhibitors do not target chronic myeloid leukemia (CML) stem cells. Most patients elapse 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 Sd-tTa-BCR-ABL1 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. and linage-SCA-1(+)C-KIT+ 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+C-KTP cells and hematopoiesis, decreased leukemia burden, significantly prolonged the survival of mice engrafted with BM cells from Sd-tTa-BCR-ABL1 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.