martes, 22 de abril de 2014

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

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



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

Nature Genetics
 
 
doi:10.1038/ng.2949
Received
 
Accepted
 
Published online
 
Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL)1, and polysomy 21 is the most frequent somatic aneuploidy among all B-ALLs2. 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.

At a glance

Figures

left
  1. Segmental trisomy orthologous to human chromosome 21q22 promotes progenitor B cell transformation.
    Figure 1
  2. Polysomy 21 B-ALL is associated with the overexpression of PRC2 targets.
    Figure 2
  3. Ts1Rhr B cells have reduced H3K27me3 that results in overexpression of bivalently marked genes.
    Figure 3
  4. HMGN1 overexpression decreases H3K27me3 and promotes transformed B cell phenotypes.

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