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

Andrew A. Lane*, Bjoern Chapuy, Charles Y. Lin, Trevor Tivey, Hubo Li, Elizabeth C. Townsend, Diederik Van Bodegom, Tovah A. Day, Shuo Chieh Wu, Huiyun Liu, Akinori Yoda, Gabriela Alexe, Anna C. Schinzel, Timothy J. Sullivan, Sébastien Malinge, Jordan E. Taylor, Kimberly Stegmaier, Jacob D. Jaffe, Michael Bustin, Geertruy Te KronnieShai Izraeli, Marian H. Harris, Kristen E. Stevenson, Donna Neuberg, Lewis B. Silverman, Stephen E. Sallan, James E. Bradner, William C. Hahn, John D. Crispino, David Pellman, David M. Weinstock

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)618-623
Number of pages6
JournalNature Genetics
Volume46
Issue number6
DOIs
StatePublished - Jun 2014

ASJC Scopus subject areas

  • Genetics

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