AFF4, a member of the AF4/FMR2 (AFF) family, is a scaffold protein in the super elongation complex (SEC). It functions as a transcription elongation factor, playing a crucial role in regulating the transcription of various genes by mobilizing paused RNA polymerase II (Pol II). AFF4 is involved in multiple biological pathways, and its dysregulation is associated with various human diseases [1,2,3,4,5,6,7]. Genetic models, such as knockout (KO) or conditional knockout (CKO) mouse models, have been valuable in studying AFF4's functions.

In adipogenesis, adipose-specific Aff4 knockout mice showed that AFF4 deficiency impedes adipocyte development and white fat depot formation, as AFF4 regulates autophagy during this process by directly binding to and promoting the transcription of autophagy-related proteins ATG5 and ATG16L1 [1]. In pancreatic tumorigenesis, loss of AFF4 impairs cell proliferation, colony formation, and cell cycle progression of pancreatic ductal carcinoma (PDAC) cells. The PI3K/c-Myc/AFF4 axis promotes PDAC by upregulating nucleotide metabolism-related enzymes HPRT1 and IMPDH2 [2].

In odontogenic and osteogenic differentiations, depletion of AFF4 in relevant cells leads to decreased differentiation potential, while overexpression enhances it. For example, in human dental pulp cells, AFF4 regulates the transcription of NFIC, a key factor for tooth root formation [3]. In human dental follicle cells, AFF4 promotes osteogenic differentiation by upregulating the transcription of ALKBH1, a critical epigenetic regulator [4].

In melanoma, AFF4 expression is upregulated, and knockdown in a xenograft mouse model showed that it promotes melanoma cell invasion and migration by regulating c-Jun activity [5]. In colorectal cancer, AFF4 is downregulated, and its deficiency promotes metastasis in vivo, as AFF4 upregulates the transcription of CDH1, which suppresses epithelial-mesenchymal transition (EMT) [7].

In conclusion, AFF4 plays essential roles in multiple biological processes, including adipogenic, odontogenic, and osteogenic differentiations. Its dysregulation is linked to diseases such as pancreatic cancer, melanoma, and colorectal cancer. The use of Aff4 KO/CKO mouse models has significantly contributed to understanding its role in these disease areas, providing insights into potential therapeutic targets.