Decoding of exon splicing patterns in the human RUNX1–RUNX1T1 fusion gene

Grinev, Vasily V.; Migas, Alexandr A.; Kirsanava, Aksana D.; Mishkova, Volha; Siomava, Natalia; Ramanouskaya, Tatsiana V.; Vaitsiankova, Alina V.; Ilyushonak, Ilia M.; Nazarov, Petr V.; Vallar, Laurent; Алейникова, О. В.

doi:10.1016/j.biocel.2015.08.017

Cited by 7 publications

(8 citation statements)

References 57 publications

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“…We found that uni-and multisplice sites involved in splicing process in Kasumi-1 cells followed the pure or truncated power-law. This finding is consistent with our previous observation on behaviour of RUNX1-RUNX1T1 exons flanked by constitutive and alternative splice sites (14). These results are of great importance since a precise definition of the distribution makes it possible to correctly describe data, formulate reasonable hypotheses about mechanism(-s) that drives these data, predict properties and capacities of the object of interest, and improve the quality of future investigations.…”

Section: Discussionsupporting

confidence: 91%

“…In our recent work, we used the RUNX1-RUNX1T1 fusion gene, present in the t(8;21)-positive acute myeloid leukemia (AML) cells, to show that distribution of exons flanked by constitutive and alternative splice sites follows the power-law (14). In that work, we identified features (potential determinants) associated with the power-law behavior of RUNX1-RUNX1T1 exons during splicing.…”

Section: Introductionmentioning

confidence: 99%

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Splice sites obey the power-law during splicing in leukemia cells

Grinev

Siomava

Vallar

et al. 2021

Preprint

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Alternative splicing is an essential characteristic of living cells that usually infers a various exon-exon junction governed by different splice sites. The traditional classification based on the mode of use designates splice site to one of the two groups, constitutive or alternative. Here, we considered another criterion and reorganized splice sites into "unisplice" and "multisplice" groups according to the number of undertaken splicing events. This approach provided us with a new insight in the organization and functionality of leukemia cells. We determined features associated with uni- and multisplice sites and found that combinatorics of these sites follows strict rules of the power-law in the t(8;21)-positive leukemia cells. We also found that system splicing characteristics of the transcriptome of leukemia cells remained persistent after drastic changes in the transcript composition caused by knockdown of the RUNX1-RUNX1T1 oncogene. In this work, we show for the first time that leukemia cells possess a sub-set of unisplice sites with a hidden multisplice potential. These findings reveal a new side in organization and functioning of the leukemic cells and open up new perspectives in the study of the t(8;21)-positive leukemia.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Splice sites obey the power-law during splicing in leukemia cells

Grinev

Siomava

Vallar

et al. 2021

Preprint

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“…Around 60% of the differential splicing events in Kasumi-1 cells cannot be explained by proximal RUNX1/RUNX1T1 binding indicating that they are not under direct control of the fusion protein. However, we and others have previously shown that t(8;21)-positive leukemia cells have a specific signature of genes encoding splicing factors and mRNA surveillance genes expression that may affect splicing patterns and abundance of RNA isoforms 35,[47][48][49][50][51][52] . This signature is so unique that it allows distinguishing leukemic from normal hematopoietic cells (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 85%

RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia

et al. 2021

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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.

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“…Similar to BCR ‐ ABL , we know little about the proteins that facilitate the extensive alternative splicing of the RUNX1 ‐ RUNX1T1 . One study attempted to begin to address this issue by examining the diversity of fusion transcripts present in AML cell lines and tumor samples and linking this to the recognition sequence motifs of different RNA processing proteins (Grinev et al, ). An analysis of over 100 possible RUNX1‐RUNX1T1 variant transcripts revealed a diverse pool of full‐length and truncated mRNA products formed from over 150 splicing events that map to 23 reference exons.…”

Section: Oncogenic Fusion Transcripts—partners In Cancermentioning

confidence: 99%

Fusion transcripts: Unexploited vulnerabilities in cancer?

2019

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Gene fusions are an important class of mutations in several cancer types and include genomic rearrangements that fuse regulatory or coding elements from two different genes. Analysis of the genetics of cancers harboring fusion oncogenes and the proteins they encode have enhanced cancer diagnosis and in some cases patient treatment. However, the effect of the complex structure of fusion genes on the biogenesis of the resulting chimeric transcripts they express is not well studied. There are two potential RNA‐related vulnerabilities inherent to fusion‐driven cancers: (a) the processing of the fusion precursor messenger RNA (pre‐mRNA) to the mature mRNA and (b) the mature mRNA. In this study, we discuss the effects that the genetic organization of fusion oncogenes has on the generation of translatable mature RNAs and the diversity of fusion transcripts expressed in different cancer subtypes, which can fundamentally influence both tumorigenesis and treatment. We also discuss functional genomic approaches that can be utilized to identify proteins that mediate the processing of fusion pre‐mRNAs. Furthermore, we assert that an enhanced understanding of fusion transcript biogenesis and the diversity of the chimeric RNAs present in fusion‐driven cancers will increase the likelihood of successful application of RNA‐based therapies in this class of tumors.This article is categorized under:RNA Processing > RNA Editing and ModificationRNA Processing > Splicing Regulation/Alternative SplicingRNA in Disease and Development > RNA in Disease

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Decoding of exon splicing patterns in the human RUNX1–RUNX1T1 fusion gene

Cited by 7 publications

References 57 publications

Splice sites obey the power-law during splicing in leukemia cells

Splice sites obey the power-law during splicing in leukemia cells

RUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia

Fusion transcripts: Unexploited vulnerabilities in cancer?

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