2019年8月12日出版的《癌细胞》杂志发表了一项最新研究成果。来自德国马丁路德·哈勒维腾贝格大学的Jan-Henning Klusmann、Dirk Heckl研究组和牛津大学Paresh Vyas研究组，合作揭示了唐氏综合征患儿髓系白血病前期向髓系白血病转化的进展机制。

唐氏综合征（ML-DS）中的髓系白血病是从短暂的异常骨髓细胞生成（TAM，DS新生儿的白血病前期）发展形成。为了确定白血病转化的机制，研究人员联合分析了111个TAM和141个ML-DS样本的外显子组和靶向重测序与功能。TAM需要21-三体（3条21号染色体）以及截短的GATA1突变；其他的TAM突变通常不致病。相反，在ML-DS中，功能上需要克隆和亚克隆变体。研究人员在骨髓细胞因子受体CSF2RB中发现了复发性和致癌性功能获得性热点突变。通过小鼠TAM体内模型中的多重CRISPR / Cas9筛选，研究人员测试了22个ML-DS高频突变基因的功能丧失。18种不同基因的丢失产生了表型、遗传和转录相似的ML-DS白血病。

附：英文原文

Title: Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome

Author: Maurice Labuhn, Kelly Perkins, Sren Matzk, Paresh Vyas, Dirk Heckl, Jan-Henning Klusmann

Issue&Volume:Volume 36 Issue 2

Abstract: Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.

DOI: https://doi.org/10.1016/j.ccell.2019.06.007

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30298-3