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

ORGANISM(S): Mus musculus

SUBMITTER: David Weinstock 

PROVIDER: E-GEOD-48553 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress