Lane Andrew A, Chapuy Bjoern, Lin Charles Y, Tivey Trevor, Li Hubo, Townsend Elizabeth C, van Bodegom Diederik, Day Tovah A, Wu Shuo-Chieh, Liu Huiyun, Yoda Akinori, Alexe Gabriela, Schinzel Anna C, Sullivan Timothy J, Malinge Sébastien, Taylor Jordan E, Stegmaier Kimberly, Jaffe Jacob D, Bustin Michael, te Kronnie Geertruy, Izraeli Shai, Harris Marian H, Stevenson Kristen E, Neuberg Donna, Silverman Lewis B, Sallan Stephen E, Bradner James E, Hahn William C, Crispino John D, Pellman David, Weinstock David M
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Nat Genet. 2014 Jun;46(6):618-23. doi: 10.1038/ng.2949. Epub 2014 Apr 20.
Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL), and polysomy 21 is the most frequent somatic aneuploidy among all B-ALLs. Yet the mechanistic links between chromosome 21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chromosome 21q22 confers mouse progenitor B cell self renewal in vitro, maturation defects in vivo and B-ALL with either the BCR-ABL fusion protein or CRLF2 with activated JAK2. Chromosome 21q22 triplication suppresses histone H3 Lys27 trimethylation (H3K27me3) in progenitor B cells and B-ALLs, and 'bivalent' genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Overexpression of HMGN1, a nucleosome remodeling protein encoded on chromosome 21q22 (refs. 3,4,5), suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.
唐氏综合征使B细胞急性淋巴细胞白血病（B-ALL）的发病风险增加20倍，而21号染色体三体是所有B-ALL中最常见的体细胞非整倍体。然而，21号染色体三倍体与B-ALL之间的机制联系仍不明确。在此我们表明，仅31个与人类21号染色体q22直系同源的基因发生种系三倍体，可赋予小鼠祖B细胞体外自我更新能力、体内成熟缺陷以及由BCR-ABL融合蛋白或激活JAK2的CRLF2导致的B-ALL。21号染色体q22三倍体抑制祖B细胞和B-ALL中的组蛋白H3赖氨酸27三甲基化（H3K27me3），并且在野生型祖B细胞中其启动子同时具有H3K27me3和H3K4me3的“双价”基因在三倍体细胞中优先过表达。具有21号染色体三体的人类B-ALL的特征是其在多种细胞类型中过表达标记有H3K27me3的基因。HMGN1（一种在21号染色体q22上编码的核小体重塑蛋白）的过表达抑制H3K27me3，并促进体外B细胞增殖和体内B-ALL发生。
