Fig. 1

An overview of the KMT2A gene, Its structure, and rearrangements. (A) Gene Structure and Key Regions. The KMT2A gene on chromosome 11 band q23.3 (11q23.3) spans about 97 Kb with 37 exons coding a large nuclear protein. Its structure is organized into regions: exons 1–3 encode the Menin-binding domain (MBD) and AT-hook motifs, which contribute to DNA binding; exons 4–9 aid in transcription regulation by coding nuclear localization signals (SNL1, SNL2) and repression domains (RD1, RD2); exons 10–27 facilitate protein interaction regions, including PHD fingers (PHD1-3) and the bromodomain (BRD); and exons 28–37 are involved in histone methylation by the transactivation domain (TAD) and SET domain. A key hotspot for chromosomal breaks and translocations, the breakpoint cluster region (BCR) frequently includes major BCR, which occurs between exons 8 and 10, and minor BCR, which occurs around exon 14. It often experiences breaks leading to potential gene fusions. (B) post-translation processing. Once the KMT2A protein is translated, it is split into two fragments by Taspase-1. This cleavage produces the N-terminal fragment (KMT2A-N) and the C-terminal fragment (KMT2A-C). The KMT2A-C contain the SET domain, crucial for adding methyl groups to histone H3K4. (C) gene rearrangements and their impact. KMT2A-r occur when the gene translocate in its BCR region, fusing with various genes (such as MLLT3/AF9, MLLT10/AF10, MLLT1/ENL, or ELL). These fusions typically merge the N-terminal portion of KMT2A with segments from other genes, resulting in its C-terminal regions loss. This disruption in normal gene function is a key factor in the development of leukemia