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

被引：99

作者：

Lane, Andrew A. ^{[1
]}

Chapuy, Bjoern ^{[1
]}

Lin, Charles Y. ^{[1
]}

Tivey, Trevor ^{[1
]}

Li, Hubo ^{[2
]}

Townsend, Elizabeth C. ^{[1
]}

van Bodegom, Diederik ^{[1
]}

Day, Tovah A. ^{[1
]}

Wu, Shuo-Chieh ^{[1
]}

Liu, Huiyun ^{[1
]}

Yoda, Akinori ^{[1
]}

Alexe, Gabriela ^{[2
]}

Schinzel, Anna C. ^{[1
,3
]}

Sullivan, Timothy J. ^{[4
]}

Malinge, Sebastien ^{[5
]}

Taylor, Jordan E. ^{[3
]}

Stegmaier, Kimberly ^{[3
]}

Jaffe, Jacob D. ^{[3
]}

Bustin, Michael ^{[6
]}

te Kronnie, Geertruy ^{[7
]}

Izraeli, Shai ^{[8
,9
]}

Harris, Marian H. ^{[10
]}

Stevenson, Kristen E. ^{[11
]}

Neuberg, Donna ^{[11
]}

Silverman, Lewis B. ^{[2
]}

Sallan, Stephen E. ^{[2
]}

Bradner, James E. ^{[1
]}

Hahn, William C. ^{[1
,3
]}

Crispino, John D. ^{[12
]}

Pellman, David ^{[2
,13
]}

Weinstock, David M. ^{[1
,3
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Broad Inst, Cambridge, MA USA

[4] Harvard Univ, Sch Med, Dana Farber Canc Inst, Microarray Core, Boston, MA 02115 USA

[5] Inst Gustave Roussy, INSERM, U985, F-94805 Villejuif, France

[6] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA

[7] Univ Padua, Dept Pediat, Padua, Italy

[8] Chaim Sheba Med Ctr, Dept Pediat Hematooncol, Ramat Gan, Israel

[9] Tel Aviv Univ, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel

[10] Childrens Hosp Boston, Dept Pathol, Boston, MA USA

[11] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA

[12] Northwestern Univ, Div Hematol Oncol, Chicago, IL 60611 USA

[13] Howard Hughes Med Inst, Chevy Chase, MD USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 06期

基金：

美国国家卫生研究院; 以色列科学基金会;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; EXPRESSION; STEM; CRLF2; GENE; PROTEINS;

D O I：

10.1038/ng.2949

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL)1, and polysomy 21 is most frequent somatic aneuploidy among all B-ALLs(2). 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. 3-5), suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.

引用

页码：618 / 623

页数：6

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