Aberrant recombination involving the granzyme locus occurs in Atm−/− T-cell lymphomas

• Published in: Human molecular genetics Vol. 14; no. 18; pp. 2671 - 2684
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15-09-2005; Oxford Publishing Limited (England)
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Blotting, Northern; Cell Cycle Proteins - genetics; Cell Line, Tumor; Computational Biology; Cytogenetic Analysis; DNA Primers; DNA-Binding Proteins - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetics of eukaryotes. Biological and molecular evolution; Granzymes; In Situ Hybridization, Fluorescence; Lymphoma, T-Cell - genetics; Mice; Mice, Knockout; Microarray Analysis; Models, Biological; Molecular and cellular biology; Mutation - genetics; Protein-Serine-Threonine Kinases - genetics; Recombination, Genetic - genetics; Reverse Transcriptase Polymerase Chain Reaction; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Tumor Suppressor Proteins - genetics; Genetics; Recombination; Locus; Mutagenicity testing
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi301

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.