Transcriptomics

Dataset Information

298

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


ABSTRACT: Down syndrome (DS) confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (ALL), yet the mechanisms underlying this association are undefined.  We show that triplication of only 31 genes orthologous to the putative DS Critical Region (DSCR) on chr.21q22 is sufficient to promote B cell-autonomous self-renewal, in vivo maturation defects and leukemogenesis in concert with BCR-ABL.  DSCR triplication results in histone H3 lysine 27 (H3K27) hypomethylation at gene promoters and a transcriptional signature characterized by de-repression of genes targeted by polycomb repressor complex 2 (PRC2), which methylates H3K27.  The same signature is highly enriched among human DS-associated ALLs.  Pharmacologic inhibition of PRC2 function is sufficient to confer self-renewal in wild-type B cells while inhibition of H3K27me3 demethylases completely blocks self-renewal induced by DSCR triplication.  Finally, overexpression of the DSCR factor HMGN1, a nucleosome remodeling protein that suppresses H3K27me3, is necessary for self-renewal in B cells with DSCR triplication. Gene expression analysis of 6 samples, 3 wild-type and 3 Ts1Rhr proB cells at passage 1

ORGANISM(S): Mus musculus  

SUBMITTER: David M Weinstock   Andrew A Lane  David Weinstock 

PROVIDER: E-GEOD-48553 | ArrayExpress | 2014-04-20

SECONDARY ACCESSION(S): SRP026566GSE48553PRJNA210618

REPOSITORIES: GEO, ArrayExpress, ENA

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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]

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