PROJECT SUMMARY/ABSTRACT Non-Hodgkin’s lymphoma (NHL) is among the most common cancers and despite current therapies many patients relapse from their disease. Recent discoveries have implicated epigenetic mechanisms and non- classical oncogenic programs as dysregulated in patients with B-cell lymphoma. Protein arginine methyltransferase-5 (PRMT5), the major enzyme responsible for the arginine symmetric dimethylation of histones and non-histone proteins, plays an important role in lymphomagenesis, controlling the growth of transformed B cells. PRMT5 is overexpressed in lymphoma and may represent a novel therapeutic target for this disease. In order to assess what regulators drive resistance, we performed a genome wide CRISPR screen. Surprisingly, we uncovered the RNA binding protein MUSASHI2 (MSI2) as the top hit. MSI2 is an RNA binding protein that has been implicated as a stem related protein that is the most highly expressed in the most aggressive cancers but its role in B-cell lymphoma is not known. Our preliminary data suggests that MSI2 is highly expressed in lymphomas and reduction reduces proliferation which is further reduced by PRMT5 inhibition. We also discovered new post-translational modifications mediated by PRMT1 and PRMT5 in B-cell lymphoma and demonstrated a functional requirement for these newly discovered modifications. We propose to study this new PRMT-MSI2 axis in driving lymphomagenesis using genetic mouse models, human lymphoma cell lines and patient samples. Furthermore, we utilize technological innovations to study direct MSI2 targets and the mechanism for how MSI2 mediates resistance to PRMT5 inhibition in lymphoma. These studies have broad implication to how RBPs can become dysregulated and their function controlled by PRMTs in B-cell lymphoma.

PROJECT NARRATIVE Although molecular targeted therapy has dramatically changed how we treat cancer, the treatment for non Hodgkin’s lymphomas remains an unmet need for new therapeutic strategies. Our studies have uncovered that the MUSASHI2 (MSI2) contributes to B-cell lymphoma cell growth and drives resistance to a protein Arginine methyltransferase (PRMT) inhibitor. This proposal studies the PRMT-MSI2 axis in both mouse models and in human B-cell lymphoma to develop a new therapeutic strategy for this disease.