CRISPR studies in t(4;14) MM to define tumor cell vulnerabilities and treatment resistance mechanisms

This project focuses on functional genomic studies of t(4;14) multiple myeloma (MM) cells. “Tiling” CRISPR knockout screens of NSD2 will be performed in order to identify standardized single guide RNAs (sgRNAs) that can be applied for functional studies of this gene in t(4;14) MM cells. Genome-scale and targeted CRISPR screens will be conducted to determine gene perturbations that sensitize MM cells to NSD2 inhibitors. Moreover, building on our recent studies on MM-preferential dependencies, we will now perform additional genome-scale CRISPR screens in more t(4;14) lines in order to provide comprehensive mapping of the molecular vulnerabilities of t(4;14) MM cells. We anticipate that these studies will provide direct functional information about the specific genes/pathways that are critical for the proliferation, survival and treatment resistance of t(4;14) MM cells (as opposed to genes whose dysregulation may be very frequent in t(4;14) MM cells but not necessarily a main functional driver for the behavior of these cells).