Genomics

Dataset Information

296

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


ABSTRACT: Children with Down syndrome (DS) have a 20-fold increased risk of developing B cell acute lymphoblastic leukemia (B-ALL). Polysomy 21 (i.e., extra copies of chr.21) is also the most frequent somatic aneuploidy among all B-ALLs. Additional B-ALLs harbor intrachromosomal amplifications of chr.21q22 (iAMP21). Yet, the mechanistic links between chr.21q22 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 is sufficient to confer murine B cell self-renewal in vitro, B cell maturation defects in vivo, and B-ALL in concert with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in murine progenitor B cells and B-ALLs, and ÒbivalentÓ genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes known to be marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q22, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo. These data implicate HMGN1 overexpression and loss of H3K27me3 in progenitor B cell transformation and suggest strategies to target leukemias with polysomy 21. ChIP-seq in wild-type and Ts1Rhr B cell progenitors for H3K27ac and H3K4me3

ORGANISM(S): Mus musculus  

SUBMITTER: David M Weinstock   Andrew A Lane  David Weinstock  Charles Y Lin 

PROVIDER: E-GEOD-48534 | ArrayExpress | 2014-04-20

SECONDARY ACCESSION(S): SRP026543GSE48534PRJNA210448

REPOSITORIES: GEO, ArrayExpress, ENA

altmetric image

Publications

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

Lane Andrew A AA   Chapuy Bjoern B   Lin Charles Y CY   Tivey Trevor T   Li Hubo H   Townsend Elizabeth C EC   van Bodegom Diederik D   Day Tovah A TA   Wu Shuo-Chieh SC   Liu Huiyun H   Yoda Akinori A   Alexe Gabriela G   Schinzel Anna C AC   Sullivan Timothy J TJ   Malinge Sébastien S   Taylor Jordan E JE   Stegmaier Kimberly K   Jaffe Jacob D JD   Bustin Michael M   te Kronnie Geertruy G   Izraeli Shai S   Harris Marian H MH   Stevenson Kristen E KE   Neuberg Donna D   Silverman Lewis B LB   Sallan Stephen E SE   Bradner James E JE   Hahn William C WC   Crispino John D JD   Pellman David D   Weinstock David M DM  

Nature genetics 20140420 6


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 ac  ...[more]

Similar Datasets

2014-04-20 | E-GEOD-55629 | ArrayExpress
2014-04-20 | E-GEOD-48553 | ArrayExpress
| GSE121062 | GEO
| GSE121070 | GEO
| GSE121066 | GEO
| GSE121065 | GEO
2016-04-01 | E-GEOD-76940 | ArrayExpress
| PRJNA210616 | ENA
| PRJNA240246 | ENA
| PRJNA210448 | ENA