Splicing regulatory dynamics for precision analysis and treatment of heterogeneous leukemias
Year: 2025
Type: article
Abstract: ABSTRACT The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations is poorly understood. To reveal complex patient subtypes and putative regulators of pathogenic splicing in Acute Myeloid Leukemia (AML), we developed a new approach called OncoSplice. Among diverse new subtypes, OncoSplice identified a biphasic poor prognosis signature that partially phenocopies U2AF1 -mutant splicing, impacting thousands of genes in over 40% of adult and pediatric AML cases. U2AF1 -like splicing co-opted a healthy circadian splicing program, was stable over time and induced a leukemia stem cell (LSC) program. Pharmacological inhibition of the implicated U2AF1 -like splicing regulator, PRMT5, rescued leukemia mis-splicing and inhibited leukemic cell growth. Genetic deletion of IRAK4, a common target of U2AF1 -like and PRMT5 treated cells, blocked leukemia development in xenograft models and induced differentiation. These analyses reveal a new prognostic alternative-splicing mechanism in malignancy, independent of splicing-factor mutations. Statement of significance Using a new in silico strategy we reveal counteracting determinants of patient survival in Acute Myeloid Leukemia that co-opt well-defined mutation-dependent splicing programs. Broad poor-prognosis splicing and leukemia stem cell survival could be rescued through pharmacological inhibition (PRMT5) or target deletion (IRAK4), opening the door for new precision therapies. Competing Interests Conflict-of-interest disclosure: DTS. serves on the scientific advisory board at Kurome Therapeutics; is a consultant for and/or received funding from Kurome Therapeutics, Captor Therapeutics, Treeline Biosciences, and Tolero Therapeutics; and has equity in Kurome Therapeutics. AV has received research funding from GlaxoSmithKline, BMS, Jannsen, Incyte, MedPacto, Celgene, Novartis, Curis, Prelude and Eli Lilly and Company, has received compensation as a scientific advisor to Novartis, Stelexis Therapeutics, Acceleron Pharma, and Celgene, and has equity ownership in Throws Exception and Stelexis Therapeutics.
Source: Science Translational Medicine
Authors: Meenakshi Venkatasubramanian, Leya Schwartz, Nandini Ramachandra, Joshua Bennett, Krithika R. Subramanian, Xiaoting Chen, Shanisha Gordon-Mitchell, Ariel Fromowitz, Kith Pradhan, David Shechter, Srabani Sahu, Diane Heiser, Peggy Scherle, Kashish Chetal, Aishwarya Kulkarni, Davy Lee, Jeff Zhou, Kasiani C. Myers, Elizabeth Tseng, Matthew T. Weirauch, H. Leighton Grimes, Daniel T. Starczynowski, Amit Verma, Nathan Salomonis
Institutions: Cincinnati Children's Hospital Medical Center, University of Cincinnati, Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Prelude Therapeutics Incorporated (United States), Pacific Biosciences (United States), University of Cincinnati Medical Center
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1290304203, G1514914720, CisBP and CisBP-RNA: web resources for protein-DNA and protein-RNA binding models, Pathways to Cancer Therapeutics, Crosstalk to Histone Arginine Methylation, Unbiased identification of spliceosome vulnerabilities across cancer, A rapid spontaneous murine model of CN-AML, G566358457, G744829577, G7857636858, Cincinnati Rheumatic Diseases Resource Center, Therapeutic targeting of IRAK4 in MDS, Cincinnati Cooperative Center of Excellence in Hematology
OpenAlex ID: W4410140346