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Insertion of the CXXC domain of KMT2A into YAP1 : An unusual mechanism behind the formation of a chimeric oncogenic protein

Teku, Gabriel LU ; Nilsson, Jenny LU ; Magnusson, Linda LU ; Sydow, Saskia LU ; Flucke, Uta ; Puls, Florian ; Mitra, Shamik LU and Mertens, Fredrik LU (2023) In Genes Chromosomes and Cancer 62(11). p.633-640
Abstract

Most neoplasia-associated gene fusions are formed through the fusion of the 5′-part of one gene with the 3′-part of another. We here describe a unique mechanism, by which a part of the KMT2A gene through an insertion replaces part of the YAP1 gene. The resulting YAP1::KMT2A::YAP1 (YKY) fusion was verified by RT-PCR in three cases of sarcoma morphologically resembling sclerosing epithelioid fibrosarcoma (SEF-like sarcoma). In all cases, a portion (exons 4/5–6) encoding the CXXC domain of KMT2A was inserted between exon 4/5 and exon 8/9 of YAP1. The inserted sequence from KMT2A thus replaced exons 5/6–8 of YAP1, which encode an important regulatory sequence of YAP1. To evaluate the cellular impact of the YKY fusion, global gene expression... (More)

Most neoplasia-associated gene fusions are formed through the fusion of the 5′-part of one gene with the 3′-part of another. We here describe a unique mechanism, by which a part of the KMT2A gene through an insertion replaces part of the YAP1 gene. The resulting YAP1::KMT2A::YAP1 (YKY) fusion was verified by RT-PCR in three cases of sarcoma morphologically resembling sclerosing epithelioid fibrosarcoma (SEF-like sarcoma). In all cases, a portion (exons 4/5–6) encoding the CXXC domain of KMT2A was inserted between exon 4/5 and exon 8/9 of YAP1. The inserted sequence from KMT2A thus replaced exons 5/6–8 of YAP1, which encode an important regulatory sequence of YAP1. To evaluate the cellular impact of the YKY fusion, global gene expression profiles from fresh frozen and formalin-fixed YKY-expressing sarcomas were compared with control tumors. The effects of the YKY fusion, as well as YAP1::KMT2A and KMT2A::YAP1 fusion constructs, were further studied in immortalized fibroblasts. Analysis of differentially upregulated genes revealed significant overlap between tumors and cell lines expressing YKY, as well as with previously reported YAP1 fusions. Pathway analysis of upregulated genes in cells and tumors expressing YKY revealed an enrichment of genes included in key oncogenic signaling pathways, such as Wnt and Hedgehog. As these pathways are known to interact with YAP1, it seems likely that the pathogenesis of sarcomas with the YKY fusion is linked to distorted YAP1 signaling.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
fusion, insertion, KMT2A, sarcoma, YAP1
in
Genes Chromosomes and Cancer
volume
62
issue
11
pages
633 - 640
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:37246732
  • scopus:85160929779
ISSN
1045-2257
DOI
10.1002/gcc.23176
language
English
LU publication?
yes
id
f89da623-098c-4934-accf-800c772ef4eb
date added to LUP
2023-08-24 15:21:22
date last changed
2024-04-20 01:37:24
@article{f89da623-098c-4934-accf-800c772ef4eb,
  abstract     = {{<p>Most neoplasia-associated gene fusions are formed through the fusion of the 5′-part of one gene with the 3′-part of another. We here describe a unique mechanism, by which a part of the KMT2A gene through an insertion replaces part of the YAP1 gene. The resulting YAP1::KMT2A::YAP1 (YKY) fusion was verified by RT-PCR in three cases of sarcoma morphologically resembling sclerosing epithelioid fibrosarcoma (SEF-like sarcoma). In all cases, a portion (exons 4/5–6) encoding the CXXC domain of KMT2A was inserted between exon 4/5 and exon 8/9 of YAP1. The inserted sequence from KMT2A thus replaced exons 5/6–8 of YAP1, which encode an important regulatory sequence of YAP1. To evaluate the cellular impact of the YKY fusion, global gene expression profiles from fresh frozen and formalin-fixed YKY-expressing sarcomas were compared with control tumors. The effects of the YKY fusion, as well as YAP1::KMT2A and KMT2A::YAP1 fusion constructs, were further studied in immortalized fibroblasts. Analysis of differentially upregulated genes revealed significant overlap between tumors and cell lines expressing YKY, as well as with previously reported YAP1 fusions. Pathway analysis of upregulated genes in cells and tumors expressing YKY revealed an enrichment of genes included in key oncogenic signaling pathways, such as Wnt and Hedgehog. As these pathways are known to interact with YAP1, it seems likely that the pathogenesis of sarcomas with the YKY fusion is linked to distorted YAP1 signaling.</p>}},
  author       = {{Teku, Gabriel and Nilsson, Jenny and Magnusson, Linda and Sydow, Saskia and Flucke, Uta and Puls, Florian and Mitra, Shamik and Mertens, Fredrik}},
  issn         = {{1045-2257}},
  keywords     = {{fusion; insertion; KMT2A; sarcoma; YAP1}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{633--640}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Genes Chromosomes and Cancer}},
  title        = {{Insertion of the CXXC domain of KMT2A into YAP1 : An unusual mechanism behind the formation of a chimeric oncogenic protein}},
  url          = {{http://dx.doi.org/10.1002/gcc.23176}},
  doi          = {{10.1002/gcc.23176}},
  volume       = {{62}},
  year         = {{2023}},
}