SRP372756 PRJNA833140 GSE201831 Genome-Wide CRISPR Screen Identifies Pharmacogenomic Determinants of Blinatumomab Resistance in Acute Lymphoblastic Leukemia [RNA-seq] Blinatumomab is an efficacious immunotherapeutic agent in B-cell acute lymphoblastic leukemia (ALL). However, pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genome-wide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19. CD58 expression varied across 20 ALL moleuclar subtypes, with marked downregulation linked to PAX5 P80R mutation in leukemia. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R. Without CD58 in B-ALL, blinatumomab-induced T cell activation was abolished with transcriptomic/ epigenomic reprogramming. Finally, we screened 1,639 transcription factor genes to systematically identify regulators of CD58/CD19 expression. In conclusion, we identified novel genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization. Overall design: Total RNA was purified from human pan T cells that were incubated with leukemia cells (Parental, CD58 knock out, or CD19 knock out Nalm6 cells) with or without blinatumomab treatment by using Qiagen Rneasy Mini Kit and subsquently used for RNA-sequencing. GSE201831 pubmed 36516256 parent_bioproject PRJNA834427