Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Department of Hematology, Centro Hospitalar Universitário de São João, Porto, 4200-319, Portugal.
Science. 2021 Jul 9;373(6551). doi: 10.1126/science.abf6202.
Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 () mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.
唐氏综合征患儿发生髓性白血病的风险增加 150 倍，但易感性的机制尚不清楚。由于唐氏综合征的白血病发生起始于胎儿发育时期，我们利用基因编辑技术在人类二倍体和三倍体胎儿造血细胞中以及异种移植模型中，对白血病前起始和白血病进展的细胞和发育背景进行了研究。GATA 结合蛋白 1 () 突变在引入 21 三体长期造血干细胞时会导致短暂性白血病前状态，其中一组 21 号染色体 microRNAs 会影响白血病前状态的易感性。相比之下，向白血病的进展不依赖于 21 三体，而是通过染色体重组蛋白基因的其他突变，起源于各种干细胞和祖细胞。CD117/KIT 原癌基因（KIT）细胞介导白血病前状态和白血病的增殖，KIT 抑制作用靶向白血病前干细胞。
