Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan.
Exp Hematol. 2021 Sep;101-102:42-48.e11. doi: 10.1016/j.exphem.2021.07.005. Epub 2021 Jul 30.
Primary refractory acute myeloid leukemia (AML) is unresponsive to conventional chemotherapy and has a poor prognosis. Despite the recent identification of novel driver mutations and advances in the understanding of the molecular pathogenesis, little is known about the relationship between genetic abnormalities and chemoresistance in AML. In this study, we subjected 39 samples from patients with primary refractory AML to whole-exome and targeted sequencing analyses to identify somatic mutations contributing to chemoresistance in AML. First, we identified 49 genes that might contribute to chemotherapy resistance through the whole-exome sequencing of samples from 6 patients with primary refractory AML. We then identified a significantly higher frequency of mutations in the gene encoding BCL-6 co-repressor (BCOR) in patients with primary refractory AML through the targeted sequencing of all coding sequence of 49 genes. Notably, the presence of BCOR mutations appeared to have a negative impact on prognosis in our cohort and previous larger studies. Subsequently, to investigate the biological effect of BCOR mutations on sensitivity to anticancer drugs, we established BCOR knockout human leukemic cell lines using the CRISPR/Cas9 system. Here, BCOR knockout cell lines exhibited statistically significant reductions in sensitivity to anticancer drugs, compared with the wild-type controls both in vitro and in vivo in xenograft mouse models. In conclusion, loss-of-function BCOR mutations appear to contribute to chemotherapy resistance and may be a promising therapeutic target in primary refractory AML.
原发性难治性急性髓系白血病（AML）对常规化疗无反应，预后不良。尽管最近已经确定了新的驱动突变，并对分子发病机制有了更深入的了解，但对于 AML 中遗传异常与化疗耐药之间的关系知之甚少。在这项研究中，我们对 39 名原发性难治性 AML 患者的样本进行了全外显子组和靶向测序分析，以鉴定导致 AML 化疗耐药的体细胞突变。首先，我们通过对 6 名原发性难治性 AML 患者样本的全外显子组测序，鉴定了 49 个可能导致化疗耐药的基因。然后，通过对 49 个基因的所有编码序列进行靶向测序，我们发现原发性难治性 AML 患者中编码 BCL-6 共抑制因子（BCOR）的基因突变频率明显更高。值得注意的是，BCOR 突变的存在似乎对我们的队列和以前更大的研究中的预后有负面影响。随后，为了研究 BCOR 突变对抗癌药物敏感性的生物学影响，我们使用 CRISPR/Cas9 系统建立了 BCOR 敲除人白血病细胞系。在这里，BCOR 敲除细胞系在体外和体内异种移植小鼠模型中均表现出对抗癌药物的敏感性显著降低，与野生型对照相比。总之，失活功能的 BCOR 突变似乎导致化疗耐药，可能是原发性难治性 AML 的一个有前途的治疗靶点。
