|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Lane, AA, Chapuy, B, Lin, CY, Tivey, T, Li, H, Townsend, EC, van Bodegom, D, Day, TA, Wu, SC, Liu, H, Yoda, A, Alexe, G, Schinzel, AC, Sullivan, TJ, Malinge, S, Taylor, JE, Stegmaier, K, Jaffe, JD, Bustin, M, Te Kronnie, G, Izraeli, S, Harris, MH, Stevenson, KE, Neuberg, D, Silverman, LB, Sallan, SE, Bradner, JE, Hahn, WC, Crispino, JD, Pellman, D, Weinstock, DM|
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.