JGM, Humans, Proto-Oncogene Proteins c-bcl-2, Myeloid Cell Leukemia Sequence 1 Protein, Cell Line, Tumor, Bridged Bicyclo Compounds, Heterocyclic, RNA Splicing, Leukemia, Myeloid, Acute, Protein-Tyrosine Kinases, Apoptosis, RNA-Binding Proteins
Cancer Cell. 2022;41:164-80.
O.A.-W. and R.K.B. were supported by the Edward P. Evans Foundation, NIH/ National Cancer Institute (NCI) (R01 CA251138), and NIH/National Heart, Lung, and Blood Institute (NHLBI) (R01 HL128239). O.A.-W. was supported by the NIH/NCI (R01 CA242020 and P50 CA254838-01) and The Leukemia & Lym- phoma Society. R.K.B. was supported by the NIH/NHLBI (R01 HL151651) and the Blood Cancer Discoveries Grant program through the Leukemia & Lymphoma Society, Mark Foundation for Cancer Research, and Paul G. Allen Frontiers Group (8023-20). R.K.B. is a Scholar of The Leukemia & Lymphoma Society (1344-18) and holds the McIlwain Family Endowed Chair in Data Sci- ence. W.J.K. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award number T32GM007739 to the Weill Cornell/Rockefeller/Sloan Kettering Tri- Institutional MD-PhD Program. Computational studies were supported in part by FHCRC’s Scientific Computing Infrastructure (ORIP S10 OD028685). We acknowledge the use of the Integrated Genomics Operation Core, sup- ported by the NCI Cancer Center Support Grant (CCSG; P30 CA08748), Cycle for Survival, and the Marie-Jose ́ e and Henry R. Kravis Center for Molecular Oncology.
Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.
Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia. Cancer Cell. 2022;41:164-80.