Lane, AndrewChapuy, BjoernLin, Charles Y.Tivey, TrevorLi, HuboTownsend, Elizabeth C.van Bodegom, DiederikDay, TovahWu, Shuo-ChiehLiu, HuiyunYoda, AkinoriAlexe, GabrielaSchinzel, AnnaSullivan, Timothy J.Malinge, SébastienTaylor, Jordan E.Stegmaier, KimberlyJaffe, Jacob D.Bustin, Michaelte Kronnie, GeertruyIzraeli, ShaiHarris, MarianStevenson, Kristen E.Neuberg, DonnaSilverman, LewisSallan, StephenBradner, James EHahn, WilliamCrispino, John D.Pellman, DavidWeinstock, David2015-01-052014Lane, A. A., B. Chapuy, C. Y. Lin, T. Tivey, H. Li, E. C. Townsend, D. van Bodegom, et al. 2014. “Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 lysine 27 trimethylation.” Nature genetics 46 (6): 618-623. doi:10.1038/ng.2949. http://dx.doi.org/10.1038/ng.2949.1061-4036http://nrs.harvard.edu/urn-3:HUL.InstRepos:13581104Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL)1 and polysomy 21 is the most frequent somatic aneuploidy amongst all B-ALLs2. Yet, the mechanistic links between chr.21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 confers murine progenitor B cell self-renewal in vitro, maturation defects in vivo, and B-ALL with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses 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. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q223–5, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.en-USJournal Article2015-01-0510.1038/ng.2949