Aberrant alternative splicing is increasingly recognized as a fundamental driver of cancer initiation and progression. The splicing factor 3b (SF3b) complex, an essential component of the U2 small nuclear ribonucleoprotein (snRNP), plays a pivotal role in branch point sequence (BPS) recognition and in coordinating spliceosome assembly and activation. Recent advances in cryo-electron microscopy (cryo-EM) have revealed the structural plasticity of the SF3b complex, highlighting its dynamic transition between open and closed conformations that stabilize pre-mRNA substrates during the splicing cycle. Genetic and functional perturbations of SF3b, particularly recurrent mutations in its core subunit SF3B1, are frequently observed in human malignancies, most prominently in myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). These alterations reshape splice site selection, generate aberrant transcript isoforms, and reprogram cancer-relevant signaling pathways. In this review, we integrate current knowledge of the molecular architecture and regulatory dynamics of the SF3b complex with its emerging roles in cancer-associated splicing programs. We discuss the consequences of SF3b mutations and non-mutational dysregulation on transcriptome remodeling, genome stability, and tumor cell fitness, as well as the contribution of post-translational modifications of SF3b components to splicing control. Furthermore, we critically evaluate recent progress in targeting the SF3b complex, focusing on the structural basis of SF3b inhibitors, insights gained from preclinical studies, and lessons learned from early-phase clinical trials. Collectively, this review positions the SF3b complex as a disease-modifying hub at the intersection of RNA splicing and cancer biology, and highlights the opportunities and challenges associated with therapeutically targeting spliceosome components in oncology.
Shulin Li, Li-Tong Shang, Jiayi Yang et al.· Blood Advances· 0 citations
Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in B-cell malignancies, but its application in acute myeloid leukemia (AML) and renal cell carcinoma (RCC) remains challenging due to the lack of ideal target antigens. CD70 is highly expressed on AML and RCC tumor cells, while its expression in normal tissues is largely restricted to activated lymphocytes, making it a promising immunotherapeutic target. However, CD70 expression on activated T cells can trigger fratricide in CD70-targeted CAR-T cells, posing a major challenge for their preparation and efficacy. Using an analog of the clinical-stage anti-CD70 antibody ARGX-110 as a reference, we screened a phage display library from immunized mice and identified high-affinity anti-CD70 antibodies, which were then used to construct a panel of second-generation CARs. Functional characterization identified a lead candidate, A174-CAR-T, with high CAR expression, strong in vitro antitumor activity, and low fratricide. We further humanized its single-chain variable fragment to generate A174-hu1-CAR. Compared with the parental construct, A174-hu1-CAR-T cells exhibited enhanced expansion and markedly reduced surface expression of CD70, consistent with improved cis-masking (i.e., surface shielding on the same cell). Molecular docking and surface electrostatic potential analyses suggested that humanization optimized the scFv-CD70 binding interface, which together with increased CAR surface expression contributed to the enhanced masking and reduced fratricide. Functionally, A174-hu1-CAR-T cells maintained potent cytotoxicity and showed enrichment of proliferative and central memory T-cell subsets. In xenograft models, A174-hu1-CAR-T infusion demonstrated potent antitumor efficacy against both AML and RCC, with a favorable safety profile. Overall, we developed a humanized CD70-targeted CAR-T cell therapy, A174-hu1-CAR-T, with reduced fratricide and potent antitumor activity, providing a preclinical foundation to support further translational development.
Meng-Jia Zhang, Zhihao Wang, Cheng Gao et al.· International Immunopharmaco...· 0 citations
