Abstract
Human chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease, and immunoglobulin heavy variable region (IGHV) gene mutational status is an important prognostic marker. IGHV mutational status has not been previously examined in canine CLL. We sequenced the IGHV-D-J rearrangements from 55 canine patients with CLL, including 36 non-Boxer and 19 Boxer dogs. The majority of non-Boxers (75%) had mutated IGHV genes, whereas the majority of Boxers (79%) had unmutated IGHV genes. IGHV3-41 and IGHV3-67 gene usage was significantly higher in Boxers with CLL compared to non-Boxers. Additionally, 11 Boxers with large B-cell lymphoma and the normal IGHV repertoire of six control dogs (three Boxers and three non-Boxers) were sequenced. IGHV3-41 was preferentially used in Boxers with other forms of lymphoma and without lymphoproliferative disease. However, preferential use of unmutated IGHV genes was unique to Boxers with CLL, suggesting Boxers may be a valuable model to investigate unmutated CLL.
Highlights
Human chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in the Western world [1,2]
We investigated immunoglobulin heavy variable region (IGHV) gene usage and mutational status in canine patients with CLL
Among non-Boxer patients with CLL, we found that the majority of cases (75%) were mutated, using the homology cut-off value of 98% as established in human CLL
Summary
Human chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in the Western world [1,2]. The disease has a variable clinical course, with wide ranges in time to progression and survival [3]. Analysis of the immunoglobulin genes has been crucial in understanding CLL pathogenesis and identifying subsets of patients with different clinical courses. Studies identified restricted immunoglobulin heavy variable region (IGHV) gene usage in CLL compared to normal B-cells [4]. Studies demonstrated that the mutational status of the IGHV genes is highly prognostic and divides patients into subsets with different clinical outcomes [5,6]. Subsets of unrelated CLL individuals were found to have highly similar to identical B-cell receptor immunoglobulins (stereotyped BCR) [7], which allowed for further stratification of patients and prognostication for certain subsets
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