Using in vivo CRISPR/Cas9 knockout screening, several putative targets were identified which might be capable to re-sensitize resistant derivatives of ALL-199 towards chemotherapy, including BCL2, COPS2 and BRIP1. Translational relevance of our results is supported by clinical data, where venetoclax and other BH3 mimetics are increasingly used in combination treatment in a wide range of different tumors [36, 37], including resistant ALL (NCT03808610, NCT03319901, NCT03504644). This evidence concerns the gene BRIP1 and acute lymphoblastic leukemia.