In 2015, we collaborated with investigators at the Fox Chase Cancer Center to study the mechanisms involved in development of B cell tumors in mice that have many histopathologic similarities to human chronic lymphocytic leukemia (CLL). The results demonstrated that the mouse tumors derived from a subset of early developing B 1 cells, and had a series of molecular features in common with human CLL including loss of a chromosomal region syntenic with human 13q14 and unmuted immunoglobulin V regions. These mice provide a novel model for understanding the pathogenesis of and developing new approaches to treatment of a subset of unmutated human CLL. SJL mice are known to develop post germinal center B cell lineage lymphomas at high frequency when less than a year of age. Studies of parallel human lymphomas showed that a significant proportion were associated with increased expression of IL21, a cytokine that is expressed at high levels by a subset of human CD4-positive T cells termed T follicular helper cells (Tfh). We found that the frequencies of Tfh were significantly increased in lymphoid tissues of SJL mice in association with high levels of circulating IL21. We examined the importance of IL21 to disease by studying SJL mice lacking the IL21 receptor and thus unable to respond to IL21. These mice had substantially reduced frequencies of Tfh and serum levels of IL21 and did not develop any B cell tumors through a year of age. We found that the histologic and molecular features of SJL disease had significant similarities to human angioimmunoblastic T cell lymphoma (AITL), now recognized as a malignancy of Tfh. Analyses of RNA prepared from archival samples of AITL revealed that essentially all cases had elevated levels of transcripts for IL21, the IL21 receptor and genes involved in the development of Tfh. These results suggested that interventions directed at interrupting the IL21 signaling pathway might be useful in treating AITL. We continue to be active in efforts to improve the classification systems for mouse hematopoietic neoplasms as they relate to similar human neoplasms. It is important for pathologists to be able to discriminate between hematopoietic neoplasms and non-malignant reactive lesions in the mouse and we have developed guidelines for making these determinations. Finally, we contributed to establishing a mouse lymphoma database at the Jackson Laboratory for identifying mouse models of human lymphomas.
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