Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Cancer Sci. 2019 Oct;110(10):3358-3367. doi: 10.1111/cas.14160. Epub 2019 Sep 10.
Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non-DS-ALL), those with DS and ALL (DS-ALL) harbor uncommon genetic alterations, suggesting DS-ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS-ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS-ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non-DS-ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome-like subtype, a high-risk B-cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS-ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS-ALL, but not non-DS-ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B-cell precursors might be associated with increased incidence of B-cell precursor ALL in DS patients.
唐氏综合征（DS）患儿罹患急性淋巴细胞白血病（ALL）的风险增加 20 倍。与无 DS 的 ALL 患儿（非 DS-ALL）相比，DS 合并 ALL（DS-ALL）患儿存在罕见的遗传改变，提示 DS-ALL 可能具有独特的生物学特征。最近的研究表明，21 号染色体上的几个基因与 DS-ALL 有关，但导致 DS 患儿易患 ALL 的确切机制尚不清楚。我们的综合遗传/表观遗传分析表明，DS-ALL 高度异质，存在多种亚型。尽管每种亚型的遗传/表观遗传特征与非 DS-ALL 中发现的相似，但两组之间的亚型分布存在显著差异。费城染色体样亚型是一种高危 B 细胞谱系变异，在整个儿科 ALL 人群中相对罕见，但在 DS-ALL 中最为常见。在 DS-ALL 中也发现了 21 号染色体上 RUNX1 的高甲基化，但在非 DS-ALL 中未发现。RUNX1 对于血细胞的分化，特别是 B 细胞的分化至关重要；因此，B 细胞前体中 RUNX1 启动子的高甲基化可能与 DS 患者中 B 细胞前体 ALL 发病率的增加有关。
