Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: David Weinstock
PROVIDER: E-GEOD-48555 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description: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
2014-04-20 | E-GEOD-48553 | biostudies-arrayexpress
Project description: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 “bivalent” 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. Gene expression analysis of 8 samples, 4 wild-type and 4 HMGN1 overexpressing transgenic B cells
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Project description: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
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