Project Summary Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma caused by the DNA tumor virus Kaposi’s sarcoma-associated herpesvirus (KSHV). PEL is an unusual cancer in that no recurrent mutations have been reported in tumors. Instead, PEL requires the continued expression of virally encoded oncogenes to alter the cellular transcriptome in latently infected cells. Candidate approaches have left us with a limited view of what cellular oncogenes are required by the viral lymphoma. It is not surprising that no effective and specific therapy is available to treat this disease. We have recently identified 210 human genes, called PEL-specific oncogenic dependencies (PSODs), that are critically important for the survival of these tumor-derived cell lines using genome-wide CRISPR/Cas9 screens. We have shown that PEL cell lines exhibit a specialized requirement for the anti-apoptotic protein MCL1 despite having high levels of other related BCL2 proteins. New functions of MCL1 have started to emerge independent of its canonical role in preventing apoptosis. It is not clear whether this selective requirement for MCL1 over the other BCL2 proteins is due to a need to block a specific apoptotic stress or whether MCL1 plays a non-canonical function in PEL. Nevertheless we have shown that we can leverage this dependency by pharmacologically inhibiting MCL1 using the small molecule compound S63845. In Aim 1, I will test the therapeutic potential of S63845 for treating PEL in a xenograft mouse model. In Aim 2, I will investigate why PEL is addicted to MCL1. Specifically in Aim 2A, I will study the role of MCL1 in blocking the activities of the p53 tumor suppressor family. In Aim 2B, I will take an unbiased approach and perform CRISPR screens to identify genetic interactions of MCL1. Together, I expect that this study will uncover new insights into the biology of MCL1 in general, answer why MCL1 is important in PEL, and develop MCL1 as a new therapeutic target for this cancer. Completion of this award will open new research areas for my career as an independent investigator in viral lymphomas.