Protein MLLT3 (AF9) (MLLT3)

Protein MLLT3, commonly known as AF9, is a critical transcriptional co-activator and a member of the YEATS domain family of histone "reader" proteins (UniProt: P42568) [1]. It functions as a core component of the Super Elongation Complex (SEC), which is essential for the productive elongation of RNA polymerase II during gene transcription (PubMed: 24463520) [2]. The N-terminal YEATS domain of MLLT3 specifically recognizes and binds to acylated lysine residues on histone H3, such as H3K9ac and H3K9cr, thereby recruiting the SEC to specific chromatin loci to facilitate gene expression (PubMed: 27156450) [3]. MLLT3 is most prominently associated with hematological malignancies, particularly through the t(9;11)(p22;q23) chromosomal translocation that creates the MLL-AF9 (KMT2A-MLLT3) fusion protein, a major driver of acute myeloid leukemia (AML) (PubMed: 29213135) [5]. In addition to its role in leukemia, MLLT3 is vital for the maintenance and self-renewal of normal hematopoietic stem cells by regulating the expression of key stemness genes (PubMed: 31776511) [6]. Because of its central role in oncogenic transcription, MLLT3 is an emerging therapeutic target; research focuses on small-molecule inhibitors that block its YEATS domain to displace the SEC from chromatin and silence MLL-fusion-driven oncogenes (SGC; PubMed: 28841415) [4, 7].

Other names

AF9YEATS3Myeloid/lymphoid or mixed-lineage leukemia; translocated to, 3

Inhibition of the YEATS domain to prevent binding to acylated histones, thereby disrupting the recruitment of the Super Elongation Complex (SEC) to oncogenic genes.