The fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of acute myeloid leukemia. Here we show that the RUNX1/RUNX1T1 oncogene is a regulator of alternative RNA splicing in leukemic cells. The comprehensive analysis of RUNX1/RUNX1T1-associated splicing events identifies two principal mechanisms that underlie the differential production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start site selection, and (ii) direct or indirect control of the expression of genes encoding splicing factors. The first mechanism leads to the expression of RNA isoforms with alternative structure of the 5’-UTR regions. The second mechanism generates alternative transcripts with new junctions between internal cassettes and constitutive exons. We also show that RUNX1/RUNX1T1-mediated differential splicing affects several functional groups of genes and produces proteins with unique conserved domain structures. In summary, this study reveals alternative splicing as an important component of transcriptome re-organization in leukemia by an aberrant transcriptional regulator.
In this work, we used a comprehensive set of the fusion oncogene RUNX1-RUNX1T1 alternative exons to analyze the patterns of its mRNA generation. We found that the waste majority of alternative exons are modified variants of canonical exons, and the transcripts, including such exons, have a very low expression level. The «hot regions», including exons 4a, 6, 8b, 9, 11 and 12, produces about 80 % of such variants. Also we described a new transcription start region of RUNX1-RUNX1T1 and provide the evidences of co-expression of the fusion RNAs with normal and shortened 3′-UTRs in leukemic cells.
Grinev et al. RUNX1/RUNX1T1-mediated alternative splicing 1 RUNX1/RUNX1T1 controls alternative splicing in the t(8;21)-positive acute myeloid leukemia cells
SUMMARYThe fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of the t(8;21)-positive acute myeloid leukemia. Here we show that this oncogene is a regulator of the alternative RNA splicing for a sub-set of genes in the leukemia cells. We found two primary mechanisms underlying changes in the production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start sites selection in target genes, and (ii) direct or indirect control of the expression of the genes encoding splicing factors. The first mechanism leads to the expression of RNA isoforms with alternative structure of the 5"-UTR regions. The second mechanism generates alternative transcripts with new junctions between internal cassettes and constitutive exons. We also show that RUNX1/RUNX1T1-mediated differential splicing affects several functional groups of genes and produces proteins with unique conserved domain structures. In summary, this study reveals a novel layer of RUNX1/RUNX1T1dependent transcriptome organization in t(8;21)-positive acute myeloid leukemia.Key words: RUNX1/RUNX1T1 fusion oncogene, differential splicing, alternative transcriptional start sites, splicing factors.Grinev et al.
RUNX1/RUNX1T1-mediated alternative splicing
The main topic of this brief communication is the critical review of flaws, found in the original article «The contribution of various mechanisms to mRNA diversity of human fusion oncogene RUNX1-RUNX1T1», which was published in «Journal of the Belarusian State University. Biology» (2019, No. 2). Also authors provide new results obtained since publication.
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