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

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. Overall design: Gene expression analysis of 6 samples, 3 wild-type and 3 Ts1Rhr proB cells at passage 1