Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation [ChIP-seq]
Children with Down syndrome (DS) have a 20-fold increased risk of developing B cell acute lymphoblastic leukemia (B-ALL). Polysomy 21 (i.e., extra copies of chr.21) is also the most frequent somatic aneuploidy among all B-ALLs. Additional B-ALLs harbor intrachromosomal amplifications of chr.21q22 (iAMP21). Yet, the mechanistic links between chr.21q22 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 is sufficient to confer murine B cell self-renewal in vitro, B cell maturation defects in vivo, and B-ALL in concert with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in murine progenitor B cells and B-ALLs, and ÒbivalentÓ genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes known to be marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q22, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo. These data implicate HMGN1 overexpression and loss of H3K27me3 in progenitor B cell transformation and suggest strategies to target leukemias with polysomy 21. Overall design: ChIP-seq in wild-type and Ts1Rhr B cell progenitors for H3K27ac and H3K4me3