PROJECT SUMMARY Follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) are the most common germinal center (GC)- derived Non-Hodgkin B cell lymphomas (BCLs). Although initially exhibiting an indolent behavior, FLs end up being mostly incurable with 40-50% eventually transforming into an aggressive and lethal form of DLBCL. Although half of DLBCLs can be cured with standard chemotherapy and immunotherapy, many patients are still refractory and succumb to progressive or relapsed disease. In addition, the strong chemotherapy regimens used, even when tolerated, have deleterious side and late effects. Thus, less toxic, targeted therapies are in urgent need for this disease. Recent advances in the molecular biology of DLBCL uncovered critical pathways in the initiation and development of these neoplasms. Of particular importance are next-generation sequencing studies that identified mutations in epigenetic modifiers that led to the development of current active clinical trials using epigenetic therapies in DLBC. Among their highest recurrent disease alleles are somatic mutations affecting two closely related histone acetyltransferase (HAT) genes, Crebbp and EP300. These are frequently monoallelic, within the HAT domain and usually mutually exclusive, suggesting that they 1) might affect a common pathway and 2) residual WT expression of CREBBP and/or EP300 is required for cell survival. We have identified the protein arginine methyltransferase CARM1 (coactivator-associated arginine methyltransferase1) as an important factor to maintain the survival of CREBBP/EP300 mutated BCLs. A potent effective small molecule inhibitor of CARM1 methylation activity has been recently developed and we hypothesize that targeting CARM1 methylation activity in CREBBP/EP300 mutated BCLs causes synthetic lethality. The major goals of this proposal are to determine how inhibition of CARM1 methylation activity affects BCLs harboring CREBBP/EP300 genetic lesions and define the molecular mechanism responsible for the sensitivity of CREBBP/EP300 BCLs to CARM1 inhibition. We anticipate that the results obtained from these studies will impact our current understanding of the pathogenesis of GC-derived BCLs, by providing new insights on the mechanisms of neoplastic transformation. Altogether we ultimately expect that these results will make a strong rationale for future clinical studies using CARM1 inhibitors in Crebbp/Ep300 mutated BCLs.

PROJECT NARRATIVE The American Cancer Society estimates that in 2019 around 74,000 people will be diagnosed with non-Hodgkin Lymphoma (NHL). The majority of these tumors arise from B cells (B-NHL) at the germinal center stage of differentiation. Using mouse models of B-NHL that recapitulate the human disease, we will determine the function and potential targeting of Coactivator-Associated Arginine Methyltransferase 1 (CARM1) in NHBCL.