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

Autor: B.A. van der Reijden, Joost H.A. Martens, Nilofar Sharifi, Hendrik G. Stunnenberg, Eva M. Janssen-Megens, Joop H. Jansen, Christian M. Zwaan, Saskia M. Bergevoet, Bowon Kim, Mathijs A. Sanders, J Knijnenburg, Anna E. Marneth, Peter J. M. Valk, Maarten Fornerod, A. S. Al Hinai, T C J M Arentsen-Peters, Torsten Haferlach, Jorren Kuster, E C G Stoetman, Marie-Laure Yaspo, Niccolò Tesi, M M van den Heuvel-Eibrink, Koen H.M. Prange
Přispěvatelé: Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, Hematology, Clinical Genetics, Pediatrics
Rok vydání: 2017
Předmět:
0301 basic medicine
Transcriptional Activation
Cancer Research
Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2]
Nerve Tissue Proteins
Biology
Translocation
Genetic
Cell Line
Epigenesis
Genetic
Histones
03 medical and health sciences
Exon
Transcription (biology)
hemic and lymphatic diseases
Humans
Protein Interaction Domains and Motifs
Promoter Regions
Genetic
Molecular Biology
Gene
Regulation of gene expression
Gene Rearrangement
Gene Expression Regulation
Leukemic
Chromosomes
Human
Pair 11
Intron
Myeloid leukemia
Nuclear Proteins
Hematology
Gene rearrangement
Exons
Histone-Lysine N-Methyltransferase
Molecular biology
Introns
Leukemia
Myeloid
Acute
030104 developmental biology
KMT2A
Oncology
biology.protein
Chromosomes
Human
Pair 16
Myeloid-Lymphoid Leukemia Protein
Zdroj: Leukemia : the Journal of Normal and Malignant Hemopoiese ; Official Journal of the Leukemia Research Fund U.K.
Leukemia, 32(3), 828-836. Nature Publishing Group
Leukemia, 32, pp. 828-836
Leukemia, 32, 828-836. Macmillan Publishers Limited, part of Springer Nature.
Leukemia, 32(3), 828-836
ISSN: 0887-6924
DOI: 10.1038/leu.2017.280
Popis: 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.Leukemia advance online publication, 24 October 2017; doi:10.1038/leu.2017.280.
Databáze: OpenAIRE
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