Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation

Lane, A. A.; Chapuy, B.; Lin, C. Y.; Tivey, T.; Li, H.; Townsend, E. C.; van Bodegom, D.; Day, T. A.; Wu, S. C.; Liu, H.; Yoda, A.; Alexe, G.; Schinzel, A. C.; Sullivan, T. J.; Malinge, S.; Taylor, J. E.; Stegmaier, K.; Jaffe, J. D.; Bustin, M.; Te Kronnie, G.; Izraeli, S.; Harris, M. H.; Stevenson, K. E.; Neuberg, D.; Silverman, L. B.; Sallan, S. E.; Bradner, J. E.; Hahn, W. C.; Crispino, J. D.; Pellman, D.; Weinstock, D. M.

Nat Genet. 2014 Apr 22; 46(6):618-23

Abstract

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.

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