Abnormal intragenic transcriptional activation in the BRE gene in MLL-rearranged and MOZ-CBP+ AML

ABSTRACT: High BRE gene expression in MLL-AF9+ acute myeloid leukemia (AML) is associated with a favorable prognosis, while high MECOM expression confers a very poor prognosis. ChIP-seq and RNA-seq experiments on primary human MLL-AF9+ AML samples showed more pronounced signals in samples with high MECOM expression, explaining its high expression. Between samples from the two MLL-AF9+ AML subgroups, promoter marks were located at the same position at the MECOM locus. In contrast, intragenic active promoter marks in BRE were exclusively present in samples with outlier high BRE expression. 5’ RACE and RNA-seq showed biallelic transcription of a novel BRE transcript starting adjacent to the active promoter marks followed by downstream exons. RT-qPCR detected the novel BRE transcript in >50% of adult and childhood MLL-rearranged (n=56) but also MOZ-CBP+ AML (n=20), while it was virtually absent in other samples (n=145, p<0.0001). The novel BRE transcript and active promoter marks were also absent from large publicly available datasets, underlining the uniqueness of this novel BRE transcript. Genome-wide analyses of MLL-AF9+ samples showed abnormal intragenic H3K4me3 marks in 90 genes exclusively in high BRE samples. Of these genes, expression of exons downstream versus upstream was most discriminative for BRE. Luciferase reporter assays using the intragenic BRE promoter showed that it was transactivated by MLL-AF9. The new BRE transcript may encode a BRE isoform that lacks part of the N-terminus. Importantly, we detected a new in frame CHORD1-BRE fusion in a case with relapsed AML. The BRE fusion occurred in the same region as intragenic transcription activation in BRE in MLL-AF9+ AML. This work identifies strong abnormal intragenic transcription activation resulting in the formation of a new BRE transcript in MLL-AF9+ and MOZ-CBP+ AML. Future studies should reveal whether alternate BRE contributes to AML pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89336 | GEO | 2017/12/20

SECONDARY ACCESSION(S): PRJNA351838

REPOSITORIES: GEO