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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lane
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Tivey
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hubo
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Townsend
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Diederik
authors.initials: D
authors.lastname: van Bodegom
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tovah A
authors.initials: TA
authors.lastname: Day
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shuo-Chieh
authors.initials: SC
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Huiyun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alexe
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Schinzel
authors.affiliation: Microarray Core, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sullivan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U985, Institut Gustave Roussy, Villejuif, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Malinge
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Jordan E
authors.initials: JE
authors.lastname: Taylor
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Jaffe
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bustin
authors.affiliation: Department of Pediatrics, University of Padova, Padova, Italy.
authors.forename: Geertruy
authors.initials: G
authors.lastname: te Kronnie
authors.affiliation: 1] Department of Pediatric Hemato-Oncology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel. [2] Department of Human Molecular Genetics and Biochemsitry, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
authors.affiliation: Department of Pathology, Children's Hospital Boston, Boston, Massachusetts, USA.
authors.forename: Marian H
authors.initials: MH
authors.lastname: Harris
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Stevenson
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, Illinois, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pellman
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002891:Chromosomes, Human, Pair 21; D019175:DNA Methylation; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D020440:Gene Duplication; D024241:HMGN1 Protein / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009707:Nucleosomes / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic
chemical_list: D024241:HMGN1 Protein; D006657:Histones; D009707:Nucleosomes; D016044:Fusion Proteins, bcr-abl; D008239:Lysine
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