The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents
The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents
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DOI：
10.1182/blood-2012-11-466425
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发表时间：
2013-09-12
期刊：
影响因子：
20.3
通讯作者：
Bhatia, Ravi
中科院分区：
文献类型：
--
作者：
Dos Santos, Cedric;McDonald, Tinisha;Bhatia, Ravi
在人急性髓系白血病(AML)细胞中，SRC家族激酶(SFKs)和受体酪氨酸激酶c-Kit被激活。我们在这里显示，在AML祖细胞中，SFKs Lyn、HCK或FGR过表达和激活。用SFK和c-kit抑制剂达沙替尼选择性地抑制体外培养的人AML干/祖细胞的生长。重要的是，达沙替尼显著增加了化疗药物对能够移植免疫缺陷小鼠的AML干细胞的清除。在体内，达沙替尼治疗增强了化疗诱导的原代小鼠急性髓细胞白血病干细胞的靶向性，该干细胞能够在二次受体中再生白血病。我们的研究表明，达沙替尼联合柔红霉素对AML细胞的靶向性增强可能与抑制AKT介导的人-鼠双分钟2同源蛋白磷酸化，导致AML细胞中P53活性增强有关。达沙替尼联合化疗提供了一种提高P53活性和增强AML干细胞靶向性的新方法。
The SRC family kinases (SFKs) and the receptor tyrosine kinase c-Kit are activated in human acute myeloid leukemia (AML) cells. We show here that the SFKs LYN, HCK, or FGR are overexpressed and activated in AML progenitor cells. Treatment with the SFK and c-KIT inhibitor dasatinib selectively inhibits human AML stem/progenitor cell growth in vitro. Importantly, dasatinib markedly increases the elimination of AML stem cells capable of engrafting immunodeficient mice by chemotherapeutic agents. In vivo dasatinib treatment enhances chemotherapy-induced targeting of primary murine AML stem cells capable of regenerating leukemia in secondary recipients. Our studies suggest that enhanced targeting of AML cells by the combination of dasatinib with daunorubicin may be related to inhibition of AKT-mediated human mouse double minute 2 homolog phosphorylation, resulting in enhanced p53 activity in AML cells. Combined treatment using dasatinib and chemotherapy provides a novel approach to increasing p53 activity and enhancing targeting of AML stem cells.