Malignancies of B and T lymphocytes, termed non-Hodgkin leukemias and lymphomas (NHL), are among the most common cancers of adults. They develop when physiologic process of normal lymphoid cells are misdirected, leading to the activation of cancer-causing genes, termed oncogenes. We previously established that mice develop a spectrum of B cell lineage tumors with many parallels to similar human neoplasms. Our studies are directed first at determining how similar the tumors of the two species are so that we can understand how to develop better mouse models for human neoplasms. Relevant models would provide opportunities for understanding the mechanisms driving diseases as well as for developing new approaches to diagnosis, treatment and possibly prevention. Mechanisms known to contribute to tumor development in many species include activation of oncogenes, inhibition of tumor suppressor genes (TSG) and mutation of DNA repair genes. A second major purpose of our studies then is to determine if and how these mechanisms also contribute to mouse lymphoid cell lineage neoplasms. Finally, we believe the knowing how mutant or abnormally expressed genes contribute to tumorigenesis will direct us to important insights into how they contribute to normal T and B cell biology. These directions have led us to study a spectrum of mice that develop T or B cell lymphomas either spontaneously or following genetic manipulations that silence or aberrantly activate selected genes with much of the work being done in collaborations with scientists at the NIH and in academia. Malignancies of B and T lymphocytes, termed non-Hodgkin leukemias and lymphomas (NHL), are among the most common cancers of adults. They develop when physiologic process of normal lymphoid cells are misdirected, leading to the activation of cancer-causing genes, termed oncogenes. We previously established that mice develop a spectrum of B cell lineage tumors with many parallels to similar human neoplasms. Our studies are directed first at determining how similar the tumors of the two species are so that we can understand how to develop better mouse models for human neoplasms. Relevant models would provide opportunities for understanding the mechanisms driving diseases as well as for developing new approaches to diagnosis, treatment and possibly prevention. Mechanisms known to contribute to tumor development in many species include activation of oncogenes, inhibition of tumor suppressor genes (TSG) and mutation of DNA repair genes. A second major purpose of our studies then is to determine if and how these mechanisms also contribute to mouse lymphoid cell lineage neoplasms. Finally, we believe the knowing how mutant or abnormally expressed genes contribute to tumorigenesis will direct us to important insights into how they contribute to normal T and B cell biology. These directions have led us to study a spectrum of mice that develop T or B cell lymphomas either spontaneously or following genetic manipulations that silence or aberrantly activate selected genes with much of the work being done in collaborations with scientists at the NIH and in academia.&#8232; Oncogenic transformation of cells requires several mutations that lead to growth factor sufficiency and independence of growth suppressive effects. In humans, these mutations are often due to recurring chromosomal changes while in mice they are caused most often by mutagenic integrations of retroviral DNA into the genome. Studies of a large number of aging mice predisposed to B cell lymphomas highlighted candidate cancer genes in the Notch and NF-kB signaling pathways along with genes governing B cell lineage commitment. Indeed, current studies have identified a critical role for Notch signaling in mouse plasma cell tumors, termed plasmacytomas, (PCT). Tumor cell lies treated with an inhibitor that blocks NOTCH activation were shown to exhibit increased cell death and reduced cell cycle progression. Similar obdervations have recently been described in the parallel human disease, multiple myeloma. &#8232;B and T cells differ from all other somatic cells in that they develop physiologic single and double strand breaks (DSB) in DNA in order to generate immune receptors and diversify B cell antigen-binding avidity through somatic hypermutation (SHM) and function by class switch recombination (CSR). Both SHM and CSR are dependent on the activity of a single enzyme, AID (activation-induced cytidine deaminase) in germinal center (GC) B cells. Remarkably, studies of mice predisposed to development of GC-derived B cell lymphomas or PCT showed that AID was critical to the development of both tumor types. Other human neoplasms due to chromosomal translocations include those of mucosa-associated lymphoid tissues (MALT) termed MALT lymphomas of marginal zone type. Some of these translocations activate BCL10 or MALT1 as potential oncogenes. Collaborative studies of a BCL10 transgenic mouse showed that the animals developed clonal marginal zone B cell lymphomas. This provides the first model system for understand the oncogenic contribution of constitutively active BCL10 to MALT lymphomagenesis. Other DSB that occur during early B cell differentiation required repair by interactions of a complex set of proteins. Studies of one of these proteins, BLM, a DNA helicase, is mutated in a familial cancer syndrome termed Blood syndrome. In studies of mice homozygous for an engineered mutant allele of Blm showed that it is required to suppress tumor development in multiple tissues including tumors of early B lineage cells. Since humans deficient in activity of this protein are also predisposed to developing lymphomas, this provides the first tractable mouse model for understanding this phenomenon. The initiation and progression of lymphoid tumors is also influenced by chronic extracellular stimuli and the constitutive activation of intracellular signaling pathways that have been thought to synergize with signals driven by engagement of antigen-specific T or B cell receptors. Activated forms of the transcription factor, STAT5, are frequently seen in human lymphomas. We found that mice expressing an activated STAT5b transgene develop thymic CD8+ T cell lymphomas indicating that it can function as an oncogene. Remarkably, studies of mice rendered incapable of signaling through the T cell receptor developed accelerated lymphomas indicating that synergy between T cell receptor and STAT5 signaling was not required for disease. We also found that changes in the nature of physical barriers between the intestinal flora and the immune system can also influence lymphomagenesis. Collaborative studies showed that mice bearing a mutant collagen XIII gene were developed a variety of B cell lineage tumors in accelerated fashion. We related this increased tumor susceptibility to changes in the basement membrane underlying the intestinal epithelium caused by the mutant protein. This was associated with activation of innate immune signaling as a precursor to B cell activation and neoplasia. Finally, we continue to be active in efforts to improve the classification systems for mouse hematopoietic neoplasms as they relate to similar human neoplasms.