CRISPR screen identifies genes that sensitize AML cells to double-negative T-cell therapy

Abstract Acute myeloid leukemia (AML) remains a devastating disease in need of new therapies to improve patient survival. Targeted adoptive T-cell have achieved impressive clinical outcomes some B-cell leukemias and lymphomas but not AML. Double-negative T cells (DNTs) effectively kill blast from the majority AML patients are now being tested trials. However, blasts obtained ?30% show resistance DNT-mediated cytotoxicity; markers or mechanisms underlying this been elucidated. Here, we used targeted clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) screen identify genes that cause susceptibility DNT therapy. Inactivation Spt-Ada-Gcn5-acetyltransferase (SAGA) deubiquitinating complex components sensitized cytotoxicity. In contrast, CD64 inactivation resulted Importantly, level expression correlated strongly with sensitivity treatment. Furthermore, ectopic overcame DNTs vitro vivo. Altogether, our data demonstrate utility CRISPR/Cas9 screens uncover therapy suggest as predictive marker for response patients.