Please use this identifier to cite or link to this item: http://localhost:8080/xmlui/handle/123456789/6863
Title: A canine mastocytoma with oncogenic c-kit activation by intra-exonic alternative splicing
Authors: Li, Mengrui
Vanegas, Stephanie
R. Gonzalgo, Mia
Keywords: Mastocytoma
Gastrointestinal stromal tumor
Alternative splicing
Issue Date: 2024
Abstract: A canine mastocytoma with oncogenic c-kit activation by intra-exonic alternative splicing Mengrui Li a,b, Stephanie Vanegas a, Mia R. Gonzalgo a, Joseph A. Lacret c, Wensi Tao d, Sapna Deo a,b,e, Sylvia Daunert a,b,e,**, Jean-Marc Zingg a,b,* a Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, 33136-6129, USA b Dr. JT Macdonald Foundation Biomedical Nanotechnology Institute, University of Miami, Miami, FL, 33136, USA c Red Bird Animal Clinic, Coral Gables, FL 33155, USA d Department of Radiation Oncology, University of Miami-Miller School of Medicine, Miami, FL, 33136, USA e University of Miami Clinical and Translational Science Institute, University of Miami, Miami, FL, 33136, USA A R T I C L E I N F O Handling editor: A Angelo Azzi Keywords: Mastocytoma Gastrointestinal stromal tumor C-kit Alternative splicing Hyperthermia Evolution Intron retention Heat stress A B S T R A C T We report a subcutaneous mastocytoma in a mid-aged Italian greyhound dog with a small 41 bp genomic deletion of the c-kit gene leading to skipping of the authentic 3′-splice junction of intron 10. The shift to an alternative splice junction in exon 11 leads to a mis-spliced in-frame mRNA transcript with a 27 bp deletion of exon 11 coding for 9 amino acids in the juxtamembrane negative regulatory domain of c-kit tyrosine kinase. In the tumor, c-kit was activated as revealed by more pronounced c-kit-regulated signaling by the PI3K/Akt and Gcoupled receptor pathways. The same 9 amino acids deletion was reported in several human gastrointestinal stromal tumors (GIST) pointing to a remarkable similarity of c-kit activation by small deletions and aberrant splicing in humans and dogs, independent of exact sequence context, tumor type and location. Interestingly, the alternative splice junction in exon 11 has been conserved in Primates but less in other Orders with increased body temperature such as ruminants. We hypothesize that elevated body temperature has acted as evolutionary pressure to eliminate the alternative splice site at this hotspot. At a molecular level, hyperthermia may increase the frequency of small deletions in the c-kit gene by facilitating base slipping or hindering repair. An RT-qPCR assay was developed to detect c-kit alternative splicing in tumors and cell lines exposed to hyperthermia. The molecular mechanisms of tumorigenesis are discussed.
URI: http://localhost:8080/xmlui/handle/123456789/6863
Appears in Collections:Vol 3 2024

Files in This Item:
File Description SizeFormat 
100039.pdf5.75 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.