Mapping the cellular oncogene addictions in virally transformed primary effusion lymphoma
Speaker:
Mark Manzano, PhD
Assistant Professor, University of Arkansas Medical Sciences, Little Rock, AR
Abstract:
The Kaposi’s sarcoma-associated herpesvirus (KSHV) causes the aggressive B cell cancer, primary effusion lymphoma (PEL). It is thought that the viral latency genes rewire the infected cell to drive transformation. This process involves the constitutive activation of cellular oncogenes which are required by infected B cells. Several cellular oncogene addictions have been identified in PEL through candidate approaches including dependencies to constitutive mTOR and PI3K signaling and p53 inhibition by MDM2. Since candidate approaches are often cumbersome and only involve a few genes of interest, there remains a limited understanding of transformation by KSHV in PEL. We thus performed unbiased genome-wide CRISPR/Cas9 screens to identify host gene addictions that drive PEL. We uncovered 210 PEL-specific oncogenic dependencies (PSODs) that are required for the survival and proliferation of tumor cell lines. Using ChIP-Seq and mRNA-Seq, we furthermore show that the viral interferon regulatory factor 3 cooperates with cellular IRF4 to promote the constitutive expression of these PSODs through super-enhancers. We propose a model wherein during B cell transformation, KSHV reprograms the cellular transcriptional landscape to create oncogenic addictions through the latency gene vIRF3. Together, our work lays the foundation for future studies on the biology of KSHV transformation and the development of therapeutics for PEL.