AFF3, also known as AF4/FMR2 Family Member 3, is a component of the transcriptional super elongation complex. It plays a role in promoting the expression of genes involved in neurogenesis, development, and is associated with various biological processes such as limb dorsoventral patterning, immunoglobulin class switch recombination, and maintaining the mono-allelic expression pattern of XIST [5,6,3,4,7].

In gastric cancer, AFF3 is significantly downregulated in tumor tissues, yet higher expression is related to worse clinicopathological characteristics and prognosis. It may regulate immune cells in the tumor microenvironment and is positively correlated with tumor-infiltrating immune cells, immune checkpoints, tumor mutational burden, and microsatellite instability, suggesting its potential as a biomarker and immunotherapy target [1].

In KINSSHIP syndrome, caused by de novo variants in the degron of AFF3, mouse knock-ins and zebrafish overexpression showed that increased AFF3 levels have pathological effects. Additionally, in zebrafish, knockdowns led to neurological defects that could be rescued by human AFF3 mRNA, and missense variants in AFF3 did not rescue these phenotypes [2,6].

In prostate cancer, AR-regulated AFF3 is downregulated in castration-resistant prostate cancer. Overexpression of AFF3 restricted cancer cell proliferation and migration, increased enzalutamide sensitivity, and affected fatty acid metabolism and ferroptosis by regulating ACSL4 expression [8].

In summary, AFF3 is crucial in multiple biological processes and diseases. Studies using gene-based models like mouse knock-ins, zebrafish overexpression and knockdowns have revealed its role in neurodevelopment-related syndromes, cancer progression, and immune-related functions, providing insights into potential disease mechanisms and therapeutic targets.