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Human Molecular Genetics Advance Access originally published online on August 8, 2005
Human Molecular Genetics 2005 14(18):2671-2684; doi:10.1093/hmg/ddi301
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© The Author 2005. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oupjournals.org

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

Christopher J. Winrow1, Daniel G. Pankratz1, Cecile Rose T. Vibat2, T.J. Bowen3, Marie A. Callahan2, Amy J. Warren2, Brian S. Hilbush2, Anthony Wynshaw-Boris3, Karl W. Hasel2, Zoë Weaver4, David J. Lockhart1,5 and Carrolee Barlow1,6,*

1The Salk Institute for Biological Studies, The Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA, 2Digital Gene Technologies, Inc., 11149 North Torrey Pines Road, La Jolla, CA 92037, USA, 3Departments of Pediatrics and Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0627, USA, 4Avalon Pharmaceuticals, Inc., 19 Firstfield Road, Gaithersburg, MD 20878, USA, 5Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, CA 92121, USA and 6Brain Cells, Inc., 10835 Road to the Cure, San Diego, CA 92121, USA

* To whom correspondence should be addressed. Tel: +1 8588127615; Fax: +1 8588127630; Email: cbarlow{at}braincellsinc.com

Received May 16, 2005; Revised July 10, 2005; Accepted August 1, 2005

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.


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