IDENTIFICATION OF GENETIC PATHWAYS CONTROLLING RESISTANCE TO STANDARD COMBINATION CHEMOTHERAPY IN ACUTE MYELOID LEUKAEMIA

Abstract

Genetic aberrations and clonal evolution underpin chemoresistant and relapsed acute myeloid leukaemia (AML). We used a genome-wide CRISPR knock-out screen to identify genes which mediate resistance to Cytarabine (AraC) and Doxorubicin (Dox) in AML, informing combination therapies to potentially circumvent resistance. Cas9-expressing human AML cell lines, OCI-AML3 and MV4-11, were transduced with the Brunello gRNA library and treated with continuous or intermittent Dox/AraC (D/A), at synergistic doses sufficient to eliminate non-transduced controls, but allow outgrowth of resistant library-transduced populations. In resistant populations, gRNAs targeting AraC metabolism components, including ..