Mice transgenic for human CTLA4-CD28 fusion gene develop adult T cell leukemia/lymphoma-like lymphoma

CTLA4-CD28 gene fusion has been reported to occur in diverse types of T-cell lymphoma. The fusion event is expected to convert inhibitory signals to activating signals promoting proliferation and potentially transformation of T-cells. To test the function of the CTLA4-CD28 fusion gene in vivo, we generated a murine model that expresses the gene in a T-cell specific manner. The transgenic mice show shorter life spans and inflammatory responses including lymphadenopathy and splenomegaly. T-cells show higher levels of activation and infiltrate various organs including skin and lung. T-cells, in particular CD4+ helper T-cells, were also readily transplanted to immunocompromised mice. Transcriptomic profiling revealed that the gene expression pattern in CD4+ cells most closely resembles that of adult T cell leukemia/lymphoma (ATLL). Consistently, we detected supernumerary Foxp3+ cells in transgenic and transplanted mice. This is the first report demonstrating the transforming activity of the CTLA4-CD28 fusion gene in vivo, and this murine model should be useful in dissecting the molecular events subsequent to the mutation in ATLL. Overall design: Examination of transcriptome on wildtype and CTLA4-CD28 fusion mice by deep sequencing