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Leukemia ; 32(3): 828-836, 2018 03.
Article in English | MEDLINE | ID: mdl-28871137

ABSTRACT

Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues. In gene reporter assays, the leukemia-specific fusion protein KMT2A-MLLT3 transactivated the intragenic BRE promoter. Further epigenome analyses revealed 97 additional intragenic promoter marks frequently bound by KMT2A in AML with C-terminal BRE expression. The corresponding genes may be part of a context-dependent KMT2A-MLLT3-driven oncogenic program, because they were higher expressed in this AML subtype compared with other groups. C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML.


Subject(s)
Gene Rearrangement , Leukemia, Myeloid, Acute/genetics , Nerve Tissue Proteins/genetics , Protein Interaction Domains and Motifs/genetics , Transcriptional Activation , Translocation, Genetic , Cell Line , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 16 , Epigenesis, Genetic , Exons , Gene Expression Regulation, Leukemic , Histone-Lysine N-Methyltransferase/genetics , Histones/metabolism , Humans , Introns , Myeloid-Lymphoid Leukemia Protein/genetics , Nuclear Proteins/genetics , Promoter Regions, Genetic
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