@article{1018fff0795946d28343a4cdac0b4b03,
title = "Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation",
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.",
author = "Lane, {Andrew A.} and Bjoern Chapuy and Lin, {Charles Y.} and Trevor Tivey and Hubo Li and Townsend, {Elizabeth C.} and {Van Bodegom}, Diederik and Day, {Tovah A.} and Wu, {Shuo Chieh} and Huiyun Liu and Akinori Yoda and Gabriela Alexe and Schinzel, {Anna C.} and Sullivan, {Timothy J.} and S{\'e}bastien Malinge and Taylor, {Jordan E.} and Kimberly Stegmaier and Jaffe, {Jacob D.} and Michael Bustin and {Te Kronnie}, Geertruy and Shai Izraeli and Harris, {Marian H.} and Stevenson, {Kristen E.} and Donna Neuberg and Silverman, {Lewis B.} and Sallan, {Stephen E.} and Bradner, {James E.} and Hahn, {William C.} and Crispino, {John D.} and David Pellman and Weinstock, {David M.}",
note = "Funding Information: We thank N. Kopp and A. Schlauch for technical assistance, M. Busslinger (Research Institute of Molecular Pathology, Vienna) for the Pax5+/− mice and M. Oshimura (Tottori University) for A9 cells carrying human chromosome 21. This research was supported by the Conquer Cancer Foundation (A.A.L.), the Lauri Strauss Leukemia Foundation (A.A.L.), the Leukemia and Lymphoma Society (A.A.L.), the Alex Lemonade Stand Foundation (A.A.L., H. Li and D.P.), the US Department of Defense (C.Y.L.), the Israel Science Foundation (S.I.), the US Israel Binational Foundation (J.D.C. and S.I.), the Stellato Fund (D.M.W.), Funding Information: US National Institutes of Health/National Cancer Institute R01 awards CA15198-01 and CA172387-A01 (D.M.W.) and a Translational Research Award from the Leukemia and Lymphoma Society (J.D.C. and D.M.W.).",
year = "2014",
month = jun,
doi = "10.1038/ng.2949",
language = "English (US)",
volume = "46",
pages = "618--623",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",
}