Splicing factor 3B subunit 1 (SF3B1) is involved in pre-mRNA branch site recognition and is the target of antitumor-splicing inhibitors. Mutations inSF3B1are observed in 15% of patients with chronic lymphocytic leukemia (CLL) and are associated with poor prognosis, but their pathogenic mechanisms remain poorly understood. Using deep RNA-sequencing data from 298 CLL tumor samples and isogenicSF3B1WT and K700E-mutated CLL cell lines, we characterize targets and pre-mRNA sequence features associated with the selection of cryptic 3′ splice sites uponSF3B1mutation, including an event in theMAP3K7gene relevant for activation of NF-κB signaling. Using the H3B-8800 splicing modulator, we show, for the first time in CLL, cytotoxic effects in vitro in primary CLL samples and inSF3B1-mutated isogenic CLL cell lines, accompanied by major splicing changes and delayed leukemic infiltration in a CLL xenotransplant mouse model. H3B-8800 displayed preferential lethality towardsSF3B1-mutated cells and synergism with the BCL2 inhibitor venetoclax, supporting the potential use of SF3B1 inhibitors as a novel therapeutic strategy in CLL.

Background: SMARCA4/BRG1 protein–deficient lung adenocarcinomas and thoracic sarcoma are recently described entities that lack distinctive histological features, transcription termination factor 1 (TTF1) reactivity, and actionable driver mutations. The current diagnostic path for small lung biopsies as recommended by the World Health Organization (WHO, 2015) is likely to categorize these as non– small cell carcinoma–not otherwise specified (NSCC-NOS). The present study attempts to define the subtle but distinctive clinicopathologic features of SMARCA4/BRG1 protein-deficient thoracic tumors; highlight their unique biology; and addresses the unmet need to segregate these using a new, tissue-proficient diagnostic pathway.Methods: All lung biopsies and those from metastatic sites in patients with suspected advanced lung cancer and classified as NSCC-NOS as per WHO (2015) guidelines were subjected to BRG1 testing by immunohistochemistry. SMARCA4/BRG1 protein–deficient thoracic tumors were evaluated by an extended immunohistochemistry panel. Predictive biomarker and programmed death–ligand 1 testing was conducted in all cases.Results: Of 110 cases, nine were found to be SMARCA4/BRG1 protein-deficient; six were identified as SMARCA4/BRG1 protein–deficient lung adenocarcinomas, and three were SMARCA4/BRG1 protein-deficient thoracic sarcomas. The histology ranged from poorly differentiated to undifferentiated to rhabdoid. None of the cases showed significant expression of TTF1 or p40, and no actionable mutation was identified.Conclusions: It is difficult to separate BRG1-deficient lung adenocarcinomas and thoracic sarcomas based on morphology alone. We propose a diagnostic pathway for small biopsies of thoracic tumors to segregate these distinct entities so that they can be studied more efficaciously for new biomarkers and therapeutic options.

Renal cell carcinoma (RCC) remains a clinically challenging malignancy characterized by high heterogeneity, limited early biomarkers, and suboptimal response rates to current targeted and immune-based therapies. Increasing evidence highlights that dysregulated epigenetic mechanisms, particularly altered histone methylation, contribute to tumor progression, metabolic reprogramming, and immune escape in RCC. However, the specific regulatory networks linking epigenetic modifiers with transcriptomic rewiring and therapeutic vulnerabilities in clear cell RCC (ccRCC) remain poorly defined. In this multi-omics in silico study, we systematically screened all histone methyltransferases and identified SUV420H2 (also known as KMT5C) as the most consistently overexpressed gene associated with adverse clinical outcomes in ccRCC. SUV420H2 showed stepwise upregulation with tumor stage and grade, while promoter analysis revealed multiple significantly hypomethylated CpG sites, suggesting a potential epigenetic deregulation. Complementarily, six predicted SUV420H2-targeting miRNAs were significantly downregulated in ccRCC consistent with post-transcriptional regulatory control. SUV420H2 overexpression correlated with increased CD4⁺/CD8⁺ T-cell infiltration, indicating an association with altered immune infiltration patterns. Co-expression and enrichment analyses revealed strong associations with chromatin organization, mitotic regulation, RNA metabolic processes, and RNA splicing, from which a five-gene RNA-processing signature (KAT2A, SNRNP70, CCNL2, CLK2, AKAP17A) was derived. This signature was strongly correlated with SUV420H2 and was associated with poorer overall survival specifically in ccRCC. Drug-sensitivity profiling further showed that high SUV420H2/RNA-processing signature expression conferred increased sensitivity to FK866 (NAMPT inhibitor), topoisomerase inhibitors, and apoptosis-inducing agents, identifying potential therapeutic associations that warrant further investigation. Collectively, our findings suggest that SUV420H2 is a multi-layer dysregulated epigenetic regulator associated with ccRCC progression and highlight its RNA-processing network as a promising prognostic and therapeutic axis.