Identifying Novel Therapeutic Targets and Combination Strategies for Patients with BPDCN

Project 1: We used CRISPR interference to perform an unbiased assessment of genes that confer sensitivity or resistance totagraxofusp or to venetoclax and azacitidine when knocked down. We compared these data to RNA-sequencing of BPDCN cells at baselineand in the setting of MRD after treatment with the same drug. We identified hits in expected pathways that mediate resistance to venetoclaxand tagraxofusp. One important hit was a largely uncharacterized RNA binding protein that confers sensitivity to both treatments whendepleted. We performed eCLIP-seq to identify targets of this RNA binding protein and are currently performing experiments to understandthe mechanism of sensitization.