Lysine methyltransferase 2A (KMT2A) fusion protein (KMT2A-r)

The Lysine methyltransferase 2A (KMT2A) fusion protein, historically referred to as the Mixed Lineage Leukemia (MLL) fusion protein, arises from chromosomal translocations at the 11q23 locus (UniProt: Q03164). In these rearrangements, the N-terminus of KMT2A is fused in-frame to one of over 80 different partner proteins, most commonly AF4, AF9, or ENL (PubMed: 28813410). These fusion proteins lose their native histone methyltransferase activity but gain the ability to recruit the Super Elongation Complex (SEC) and DOT1L, leading to the epigenetic dysregulation and constitutive overexpression of homeobox (HOX) genes (PubMed: 26000481). This process arrests hematopoietic development and drives the pathogenesis of high-risk acute leukemias (NIH: StatPearls). Because the stability of the KMT2A fusion complex on chromatin depends on its interaction with the protein Menin, this interface has become a primary therapeutic target (PubMed: 36385087). Small-molecule inhibitors like Revumenib and Ziftomenib disrupt the Menin-KMT2A interaction, resulting in the downregulation of oncogenic targets and the induction of myeloid differentiation (PubMed: 37045997).

Other names

MLL fusion proteinMixed lineage leukemia fusion proteinKMT2A-rearranged proteinMLL-rHRX fusionALL-1 fusion

Inhibition of the protein-protein interaction between Menin and the KMT2A fusion protein, which prevents the recruitment of the oncogenic transcriptional complex to target gene promoters and restores normal hematopoietic differentiation.