Histone-lysine N-methyltransferase 2A (KMT2A) fusion protein (KMT2A fusion)

The Histone-lysine N-methyltransferase 2A (KMT2A) fusion protein, formerly known as the Mixed-Lineage Leukemia (MLL) fusion protein, is a chimeric oncogenic driver resulting from chromosomal translocations involving the KMT2A gene at the 11q23 locus (UniProt Q03164). These translocations fuse the N-terminal portion of KMT2A with one of over 80 different partner proteins, most commonly AF4, AF9, or ENL, leading to the constitutive activation of a leukemogenic transcriptional program (PubMed: 36913879). The fusion protein functions by recruiting epigenetic co-factors, such as the histone methyltransferase DOT1L, and requires interaction with the scaffold protein Menin to bind to its target genes, including the HOXA cluster and MEIS1 (PubMed: 21436002). This aberrant gene expression prevents hematopoietic differentiation and promotes the self-renewal of leukemic stem cells, particularly in infant acute lymphoblastic leukemia (ALL) and adult acute myeloid leukemia (AML). Therapeutic targeting of this complex has primarily focused on small-molecule inhibitors that disrupt the Menin-KMT2A interaction or inhibit DOT1L activity, aiming to reverse the epigenetic dysregulation and induce terminal differentiation of the malignant cells (ClinicalTrials.gov: NCT04065399). While the term antigen is sometimes used in the context of associated surface markers like NG2 (CSPG4), the fusion protein itself is an intracellular nuclear target rather than a classical cell-surface antigen (PubMed: 12149211).

Other names

MLL fusion proteinMLL1 fusionKMT2A-rearranged proteinMixed-lineage leukemia protein fusionKMT2A-AF4KMT2A-AF911q23 translocation product

Disruption of the Menin-KMT2A interaction or inhibition of associated methyltransferases like DOT1L to suppress the expression of oncogenic targets such as HOXA9 and MEIS1.