Abstract A03: Immunoglobulin heavy chain usage in canine CLL

Canine B cell chronic lymphocytic leukemia resembles human CLL in presentation and clinical outcomes. The disease is indolent (median survival greater than 1000 days) and presents in older dogs (median age = 10.8 years). Major differences between the human and canine disease include immunophenotype (canine B cell CLL does not express CD5) and a gender ratio in the dog that is 1:1. Risk factors for canine B cell CLL have not been identified, but three breeds are more frequently represented amongst CLL cases than in the general population of dogs with confirmed or suspected lymphoproliferative disease of any type; Boxers, Shih-tsu dogs and English Bull dogs. Remarkably, the breed which most frequently develops a variety of lymphoproliferative disorders, the Golden Retriever, is virtually absent from the population of canine CLL patients. This breed predilection suggests that as in people, genetic factors contribute significantly to risk. We hypothesized that canine B cell CLL would be a useful model for uncovering genetic risk factors for the disease, and here we report initial characterization of this model by examining immunoglobulin V gene usage and mutation status. Our findings are: 1) 34% of dogs with CLL had unmutated IgVH genes, as defined by a difference of greater than 2% from the available germline sequence, 2) While the canine genome has 85 IgH V gene segments (43 pseudogenes, 42 functional genes), almost half (42%) of the CLL cases with unmutated IgH genes used a single V gene segment, VH41; Only 9% of non-neoplastic B cells utilize VH41, and 5% of CLL cases with mutated genes use VH41; 3) All animals of the Boxer breed had unmutated IgH genes; 4) canine VH35 was used in 29% of cases with somatic hypermutation, but was not found in unmutated CLL nor in the normal canine B cell repertoire. The striking breed association and restricted V gene usage suggest that certain dog breeds such as the Boxer could provide a useful model for investigation of genetic factors leading to B cell CLL in both humans and dogs. Note: This abstract was not presented at the conference. Citation Format: Robert Burnett, Stacey George, Serena Mancha, Julia Bromerek, Anne Avery. Immunoglobulin heavy chain usage in canine CLL. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A03.