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Retroviral insertions in the VISION database identify molecular pathways in mouse lymphoid leukemia and lymphoma

Authors
  • Weiser, Keith C.1, 2
  • Liu, Bin1
  • Hansen, Gwenn M.1, 3
  • Skapura, Darlene1
  • Hentges, Kathryn E.1, 4
  • Yarlagadda, Sujatha1, 5
  • Morse III, Herbert C.6
  • Justice, Monica J.1
  • 1 Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, Texas, 77030, USA , Houston (United States)
  • 2 Baylor College of Medicine, Interdepartmental Program in Cell and Molecular Biology, One Baylor Plaza, Houston, Texas, 77030, USA , Houston (United States)
  • 3 Lexicon Genetics Inc., 8800 Technology Forest Place, The Woodlands, TX, 77381, USA , The Woodlands (United States)
  • 4 The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK , Manchester (United Kingdom)
  • 5 Harris County Forensic Biology Laboratory, 1885 Old Spanish Trail, Houston, TX, 77054, USA , Houston (United States)
  • 6 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Laboratory of Immunopathology, 9000 Rockville Pike, Bethesda, Maryland, 20892, USA , Bethesda (United States)
Type
Published Article
Journal
Mammalian Genome
Publisher
Springer-Verlag
Publication Date
Oct 10, 2007
Volume
18
Issue
10
Pages
709–722
Identifiers
DOI: 10.1007/s00335-007-9060-2
Source
Springer Nature
Keywords
License
Green

Abstract

AKXD recombinant inbred (RI) strains develop a variety of leukemias and lymphomas due to somatically acquired insertions of retroviral DNA into the genome of hematopoetic cells that can mutate cellular proto-oncogenes and tumor suppressor genes. We generated a new set of tumors from nine AKXD RI strains selected for their propensity to develop B-cell tumors, the most common type of human hematopoietic cancers. We employed a PCR technique called viral insertion site amplification (VISA) to rapidly isolate genomic sequence at the site of provirus insertion. Here we describe 550 VISA sequence tags (VSTs) that identify 74 common insertion sites (CISs), of which 21 have not been identified previously. Several suspected proto-oncogenes and tumor suppressor genes lie near CISs, providing supportive evidence for their roles in cancer. Furthermore, numerous previously uncharacterized genes lie near CISs, providing a pool of candidate disease genes for future research. Pathway analysis of candidate genes identified several signaling pathways as common and powerful routes to blood cancer, including Notch, E-protein, NFκB, and Ras signaling. Misregulation of several Notch signaling genes was confirmed by quantitative RT-PCR. Our data suggest that analyses of insertional mutagenesis on a single genetic background are biased toward the identification of cooperating mutations. This tumor collection represents the most comprehensive study of the genetics of B-cell leukemia and lymphoma development in mice. We have deposited the VST sequences, CISs in a genome viewer, histopathology, and molecular tumor typing data in a public web database called VISION (Viral Insertion Sites Identifying Oncogenes), which is located at http://www.mouse-genome.bcm.tmc.edu/vision.

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