Fms 样酪氨酸激酶 3 内部串联重复通过表观遗传激活急性髓系白血病细胞中的检查点激酶 1。
Fms-like tyrosine kinase 3-internal tandem duplications epigenetically activates checkpoint kinase 1 in acute myeloid leukemia cells.
机构信息
Department of Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China.
Department of Hematology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China.
出版信息
Sci Rep. 2021 Jun 24;11(1):13236. doi: 10.1038/s41598-021-92566-5.
It is not clear how Fms-like tyrosine kinase 3-internal tandem duplications (FLT3-ITD) regulates checkpoint kinase 1 (CHK1) in acute myeloid leukemia (AML). In this study, we investigated the regulatory effect of FLT3-ITD on CHK1. Our results showed that CHK1 was highly expressed in FLT3-ITD positive AML. The overall survival rate and disease-free survival rate of AML patients with high CHK1 level were lower than those of patients with low CHK1 level. Mechanistically, FLT3-ITD recruited p300 to the CHK1 promoter and subsequently acetylated H3K27, thereby enhancing the transcription of CHK1. Interfering with the expression of CHK1 significantly inhibited the cell proliferation and induced cell apoptosis in FLT3-ITD positive MV4-11 cells. In addition, CHK1 knockdown promoted the sensitivity of MV4-11 cells to the epigenetic inhibitors JQ1 and C646. This study discovers a new therapeutic target for FLT3-ITD + AML and provided evidence for the combination of epigenetic inhibitors for AML treatment.
FLT3-ITD 如何调节急性髓系白血病（AML）中的细胞检查点激酶 1（CHK1）尚不清楚。在这项研究中，我们研究了 FLT3-ITD 对 CHK1 的调节作用。结果表明，CHK1 在 FLT3-ITD 阳性 AML 中高度表达。CHK1 水平高的 AML 患者的总生存率和无病生存率均低于 CHK1 水平低的患者。在机制上，FLT3-ITD 将 p300 募集到 CHK1 启动子上，随后乙酰化 H3K27，从而增强 CHK1 的转录。干扰 CHK1 的表达显著抑制了 FLT3-ITD 阳性 MV4-11 细胞的增殖，并诱导其细胞凋亡。此外，CHK1 敲低促进了 MV4-11 细胞对表观遗传抑制剂 JQ1 和 C646 的敏感性。这项研究发现了 FLT3-ITD+AML 的一个新的治疗靶点，并为 AML 的表观遗传抑制剂联合治疗提供了证据。
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