Abstract
Abstract While the genetic aberrations in cancer cells have been revealing, many malignant phenotypes are regulated by genes that are not genetically altered. To gain insight into these pathways, we have employed genome-wide genetic screens using CRISPR-Cas9 technology. In one type of screen, lentiviral libraries expressing small guide RNAs (sgRNAs) are used to direct the endonuclease Cas9 to particular genomic locations, leading to the cutting and inactivation of the targeted gene. An alternative approach, called CRISPRi, uses a catalytically-dead Cas9 isoform fused to a KRAB transcriptional repressor domain. sgRNAs are used to guide this fusion protein to gene promoters, leading to their silencing. We are utilizing both screening methodologies in a variety of cell line models of various genetic subtypes of diffuse large B cell lymphoma, T cell lymphomas, and multiple myeloma, looking for essential genes that control proliferation and/or survival in a cancer subtype-specific fashion. We are also using these screens to uncover genes that synergize or antagonize targeted agents that are in clinical development in these lymphoid malignancies. I will present new Insights from these screens into the mechanisms by which lymphomas acquire sensitivity to therapeutic agents targeting B cell receptor signaling, such as ibrutinib, and how they subsequently may develop resistance. Citation Format: Louis M. Staudt. Genome-wide CRISPR screens illuminate lymphoma pathogenesis and therapeutic resistance [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA09.
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