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Nat Genet DOI:10.1038/ng.2949

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

Publication TypeJournal Article
Year of Publication2014
AuthorsLane, AA, Chapuy, B, Lin, CY, Tivey, T, Li, H, Townsend, EC, van Bodegom, D, Day, TA, Wu, S-C, Liu, H, Yoda, A, Alexe, G, Schinzel, AC, Sullivan, TJ, Malinge, S, Taylor, JE, Stegmaier, K, Jaffe, JD, Bustin, M, Kronnie, Gte, Izraeli, S, Harris, MH, Stevenson, KE, Neuberg, D, Silverman, LB, Sallan, SE, Bradner, JE, Hahn, WC, Crispino, JD, Pellman, D, Weinstock, DM
JournalNat Genet
Date Published2014 Jun
KeywordsAnimals, B-Lymphocytes, Bone Marrow Transplantation, Cell Proliferation, Chromosomes, Human, Pair 21, DNA Methylation, Female, Fusion Proteins, bcr-abl, Gene Duplication, Histones, HMGN1 Protein, Humans, Lysine, Male, Methylation, Mice, Mice, Inbred C57BL, Nucleosomes, Phenotype, Promoter Regions, Genetic

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.


Alternate JournalNat. Genet.
PubMed ID24747640
PubMed Central IDPMC4040006
Grant ListR01 CA151898 / CA / NCI NIH HHS / United States
T32 HL116324 / HL / NHLBI NIH HHS / United States
K08 CA181340 / CA / NCI NIH HHS / United States
R01 CA15198-01 / CA / NCI NIH HHS / United States
CA172387-A01 / CA / NCI NIH HHS / United States
R01 CA172387 / CA / NCI NIH HHS / United States