H-2ZHomozygous New Zealand Mice as a Model for B-Cell Chronic Lymphocytic Leukemia: Elevatedbcl-2 Expression in CD5 B Cells at Premalignant and Malignant Stages

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Abstract
In New Zealand mice, the major histocompatibility complex (MHC) controls the development of both autoimmune disease and B cell chronic lymphocytic leukemia (B‐CLL). While H‐2d/H‐2z heterozygosity acts as one major predisposing genetic element for autoimmune disease, H‐2z/H‐2z homozygosity acts as an element for B‐CLL. In the H‐2z/H‐2z homozygotes, there was an age‐dependent increase in frequencies of CD5 B cells in the blood and spleen, and such CD5 B cells showed oligoclonal to monoclonal expansion, giving rise to B‐CLL. B‐CLL cells from these mice had surface phenotypes typical of CD5 B lineage cells, and expressed high levels of proto‐oncogene bcl‐2. Elevated bcl‐2 expression was also observed in premalignant B cells in the aged mice, thereby suggesting that apoptosis‐resistant, long‐surviving CD5 B cells with a self‐renewal capacity form the basis of malignant transformation. This model not only provides clues for analyzing multiple steps of genetic alterations involved in the generation of B‐CLL, but also sheds light on the correlation between B‐CLL and autoimmune disease.