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Splicing regulatory dynamics for precision analysis and treatment of heterogenous leukemias

ABSTRACT: The role of splicing dysregulation in cancer is underscored by splicing factor mutations, however, its impact in the absence of such rare mutations remains poorly understood. Prompted by the finding that splicing uniquely resolved genetic subtypes of cancer, we developed an unsupervised computational workflow called OncoSplice to comprehensively define tumor molecular landscapes. In adult and pediatric Acute Myeloid Leukemia (AML), OncoSplice identified the spectrum of driver genetics from splicing profiles alone, defined over a dozen new molecular subtypes recurrent across AML cohorts and discovered a dominant splicing subtype that partially phenocopies U2AF1-mutant splicing. Although pediatric leukemias lack splicing factor mutations, this U2AF1-like subtype similarly spanned pediatric and adult AML genetics and consistently predicted poor prognosis. Using long-read single-cell RNA-Seq, we confirmed discovered U2AF1-like splicing was shared across cell states, co-opts a healthy circadian gene program, was stable through relapse and induced a leukemia stem cell (LSC) program. Pharmacological inhibition of the OncoSplice implicated U2AF1-like splicing regulator, PRMT5, rescued leukemia mis-splicing and inhibited leukemic cell growth. Finally, genetic deletion of IRAK4, a common target of U2AF1-like and PRMT5 treatment, blocked leukemia development in xenograft models and induced differentiation. This work suggests broad splicing dysregulation, in the absence of select mutations, is a therapeutic target in heterogenous leukemias.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292324 | GEO | 2025/07/09

REPOSITORIES: GEO

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Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation

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U2AF1 mutations alter splice site recognition in hematological malignancies

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Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and two PRMT5 inhibitors are currently in clinical trials for a range malignancies. Despite the recognized therapeutic potential, it is unclear which PRMT5 functions underlie its oncogenic activity. In this study, we aimed to further understand the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using cutting-edge proteomics techniques we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 directly regulates SRSF1 activity in leukemia, and they provide potential biomarkers for the treatment response to PRMT5 inhibitors.

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