C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation

A. E. Marneth, K. H.M. Prange, A. S.A. Al Hinai, S. M. Bergevoet, N. Tesi, E. M. Janssen-Megens, B. Kim, N. Sharifi, M. L. Yaspo, J. Kuster, M. A. Sanders, E. C.G. Stoetman, J. Knijnenburg, T. C.J.M. Arentsen-Peters, C. M. Zwaan, H. G. Stunnenberg, M. M. Van Den Heuvel-Eibrink, T. Haferlach, M. Fornerod, J. H. JansenP. J.M. Valk, B. A. Van Der Reijden, J. H.A. Martens

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

5 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)828-836
Aantal pagina's9
Nummer van het tijdschrift3
StatusGepubliceerd - 1 mrt. 2018


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