Aberrant recombination involving the granzyme locus occurs in
Authors: Winrow, Christopher J.1; Pankratz, Daniel G.1; Vibat, Cecile Rose T.2; Bowen, T.J.3; Callahan, Marie A.2; Warren, Amy J.2; Hilbush, Brian S.2; Wynshaw-Boris, Anthony3; Hasel, Karl W.2; Weaver, Zoë4; Lockhart, David J.1; Barlow, Carrolee1
Source: Human Molecular Genetics, Volume 14, Number 18, 15 September 2005 , pp. 2671-2684(14)
Publisher: Oxford University Press
Abstract:Ataxia telangiectasia (A-T) is an autosomal recessive disease caused by loss of function of the serine/threonine protein kinase ATM (ataxia telangiectasia mutated). A-T patients have a 250–700-fold increased risk of developing lymphomas and leukemias which are typically highly invasive and proliferative. In addition, a subset of adult acute lymphoblastic leukemias and aggressive B-cell chronic lymphocytic leukemias that occur in the general population show loss of heterozygosity for ATM. To define the specific role of ATM in lymphomagenesis, we studied T-cell lymphomas isolated from mice with mutations in ATM and/or p53 using cytogenetic analysis and mRNA transcriptional profiling. The analyses identified genes misregulated as a consequence of the amplifications, deletions and translocation events arising as a result of ATM loss. A specific recurrent disruption of the granzyme gene family locus was identified resulting in an aberrant granzyme B/C fusion product. The combined application of cytogenetic and gene expression approaches identified specific loci and genes that define the pathway of initiation and progression of lymphoreticular malignancies in the absence of ATM.
Document Type: Research Article
Affiliations: 1: The Salk Institute for Biological Studies, The Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA, 2: Digital Gene Technologies, Inc., 11149 North Torrey Pines Road, La Jolla, CA 92037, USA, 3: Departments of Pediatrics and Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0627, USA, 4: Avalon Pharmaceuticals, Inc., 19 Firstfield Road, Gaithersburg, MD 20878, USA,
Publication date: 2005-09-15
- Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics.
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- By this author: Winrow, Christopher J. ; Pankratz, Daniel G. ; Vibat, Cecile Rose T. ; Bowen, T.J. ; Callahan, Marie A. ; Warren, Amy J. ; Hilbush, Brian S. ; Wynshaw-Boris, Anthony ; Hasel, Karl W. ; Weaver, Zoë ; Lockhart, David J. ; Barlow, Carrolee