KMT2A

KMT2A, also known as MLL (mixed-lineage leukemia) 1, is a human gene that encodes a histone lysine methyltransferase responsible for methylating lysine 4 on histone H3 (H3K4). This epigenetic mark is associated with transcriptional activation at gene promoters and regulatory elements. KMT2A functions as a core component of COMPASS- and COMPASS-like protein complexes that regulate gene expression during development and hematopoiesis, in part by controlling HOX gene clusters.

The KMT2A protein is large and modular, containing an N-terminal region that mediates interactions with transcriptional regulators, a central region, and a C-terminal SET domain that carries methyltransferase activity. A CXXC domain binds unmethylated CpG DNA. In the native complex, KMT2A associates with core subunits such as WDR5, RbBP5, ASH2L, and DPY-30 to form the active H3K4 methyltransferase complex. In leukemia, chromosomal rearrangements often involve KMT2A at 11q23, producing MLL fusion proteins that recruit transcriptional elongation machinery and ectopically activate HOX genes, promoting leukemogenesis.

Clinical significance includes somatic KMT2A rearrangements in acute leukemias, especially in infants, which define a distinct and historically challenging subset with variable prognosis. Therapeutic approaches include targeted strategies under investigation, such as DOT1L inhibitors (aimed at the abnormal methylation pattern in MLL-rearranged leukemia) and Menin-MLL inhibitors in development.

Germline variants in KMT2A also cause Wiedemann-Steiner syndrome, a developmental disorder characterized by growth delay and distinctive features. KMT2A is located on chromosome 11q23 and encodes MLL1, a key regulator of gene expression during development and hematopoiesis.