加拿大健康网络大学Eric R. Lechman和Elvin Wagenblast研究组合作取得最新进展。他们绘制了唐氏综合征白血病的细胞起源和早期进化图。相关论文于2021年7月9日发表在《科学》杂志上。
由于唐氏综合征白血病发生在胎儿发育过程中，他们使用人类二体和三体胎儿造血细胞中的基因编辑和异种移植来表征白血病前期开始和白血病进展的细胞和发育背景。当 GATA 结合蛋白 1 (GATA1) 突变引入 21 三体长期造血干细胞时，会导致暂时性前期白血病，其中 21 号染色体 microRNA 的一个亚群影响了前期白血病的易感性。
相比之下，白血病的进展与 21 三体无关，并且通过 cohesin 基因的额外突变起源于各种干细胞和祖细胞。 CD117+/KIT原癌基因（KIT）细胞介导前期白血病和白血病的增殖，KIT抑制靶向前期白血病干细胞。
据悉，患有唐氏综合症的儿童患髓性白血病的风险增加了 150 倍，但易感性机制尚不清楚。
附：英文原文
Title: Mapping the cellular origin and early evolution of leukemia in Down syndrome
Author: Elvin Wagenblast, Joana Araújo, Olga I. Gan, Sarah K. Cutting, Alex Murison, Gabriela Krivdova, Maria Azkanaz, Jessica L. McLeod, Sabrina A. Smith, Blaise A. Gratton, Sajid A. Marhon, Martino Gabra, Jessie J. F. Medeiros, Sanaz Manteghi, Jian Chen, Michelle Chan-Seng-Yue, Laura Garcia-Prat, Leonardo Salmena, Daniel D. De Carvalho, Sagi Abelson, Mohamed Abdelhaleem, Karen Chong, Maian Roifman, Patrick Shannon, Jean C. Y. Wang, Johann K. Hitzler, David Chitayat, John E. Dick, Eric R. Lechman
Issue&Volume: 2021/07/09
Abstract: 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 (GATA1) 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.
DOI: 10.1126/science.abf6202
Source: https://science.sciencemag.org/content/373/6551/eabf6202