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.

目前尚不清楚 Fms 样酪氨酸激酶 3 内部串联重复 (FLT3-ITD) 如何调节急性髓性白血病 (AML) 中的检查点激酶 1 (CHK1)。在这项研究中，我们研究了 FLT3-ITD 对 CHK1 的调节作用。我们的结果表明 CHK1 在 FLT3-ITD 阳性 AML 中高表达。CHK1水平高的AML患者的总生存率和无病生存率低于CHK1水平低的患者。从机制上讲，FLT3-ITD 将 p300 募集到 CHK1 启动子，随后乙酰化 H3K27，从而增强 CHK1 的转录。干扰CHK1的表达可显着抑制FLT3-ITD阳性MV4-11细胞的细胞增殖并诱导细胞凋亡。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。