SF3B1 mutation

P2, N=15, Completed, National Heart, Lung, and Blood Institute (NHLBI) | Active, not recruiting --> Completed

Novel protein degrader small molecules which co-opt DCAF16 to degrade BRD4 as a neosubstrate demonstrated preferential selectivity for SF3B1 mutant cancers and CLL primary patient specimens due to increased DCAF16 protein levels. In turn, this reveals the therapeutic relevance of mutant SF3B1 dysregulation of transcript untranslated regions and uncovers a novel strategy for the treatment of these important neoplasms.

We also look into how splicing-driven PTM changes, especially those that affect ubiquitination pathways and other important modification systems, affect the immune landscape of tumors. This gives us new information about how tumors with splicing mutations become more fit by changing the pathways that control the immune system and tumor surveillance.

Targeted and genome-wide analysis of RNA splicing reveal that they affect canonical and alternative splicing more moderately than somatic variants, and subtly modify the splicing of many transcripts. These findings place SF3B1 among the rare U2 snRNP components implicated in both cancer and neurodevelopmental disorders, highlighting its critical and multifaceted role in human disease.

Here we report red blood cell (RBC) transfusion response analysis based on somatic mutations profile and disease risk for patients treated with luspatercept or epoetin alfa in the COMMANDS trial. Luspatercept represents an effective treatment option in various mutational backgrounds in LR MDS. Trial Registration: ClinicalTrials.gov Identifier: NCT03682536.

This is the first reported case of MDS-SF3B1 coexisting with clonal CD4 T-cell proliferation.

MRD of secondary type mutations alone lacks predictive value, yet MRD of non-DTA mutations in CR is associated with increased CIR in st-AML (SHR MRDpos vs. MRDneg 3.25; p<0.001). Molecularly-defined st-AML, including st-MDS/AML, defines a distinct AML category with a unique genetic, clinical and treatment response profile, in which NGS-based MRD holds markedly prognostic significance.

Our data confirmed unfavourable prognostic value of IGLV321 for prediction of progressionfree survival and overall survival in CLL patients with M IGHV genes, regardless of radiation anamnesis.

Mutation-mediated splicing abnormalities thus represent targets for new therapeutic agents such as spliceosome inhibitor pladienolide B. However, although studies have advanced our understanding of these abnormalities from basic splicing changes to effects on signaling networks and potential clinical translation, various aspects need further exploration; these include mutation-specific functional heterogeneity, interactions with the tumor microenvironment, and mechanisms of drug resistance. This review systematically summarizes the functions of SF3B1 mutations and their underlying molecular mechanisms in spliceosome-driven tumorigenesis, with the aim of providing a framework for better understanding of this process, as well as discussing prospects for new precision medicine diagnostic and treatment strategies.

Functionally, ectopic expression of ARPP19-long accelerated mitotic exit, and high ARPP19-long abundance associated with poorer overall survival in the TCGA-AML cohort. Our findings highlight a connection between SF3B1-dependent splicing, cell cycle progression, and tumorigenesis, offering new insights into the molecular mechanisms underlying cancer-associated splicing dysregulation.

This pilot study reports on cfDNA methylation signatures that differentiates UM patients from HBDs, and may distinguish between intermediate and high risk UM subgroups, supporting its prognostic potential. However, its role in monitoring disease progression requires further validation. Independent replication studies are warranted to confirm our findings and evaluate the clinical applicability in UM.