Lysine methyltransferase 2A-afadin fusion mRNA (KMT2A-AFDN)

KMT2A::AFDN fusion mRNA is a chimeric transcript resulting from the chromosomal translocation t(6;11)(q27;q23), which fuses the N-terminus of the Lysine Methyltransferase 2A (KMT2A) gene with the Afadin (AFDN) gene [PubMed 28637616]. This genetic alteration is primarily associated with aggressive forms of acute myeloid leukemia (AML) and is characterized by a poor prognosis [PubMed 25135958]. The fusion transcript encodes a chimeric protein that retains the N-terminal Menin-binding domain of KMT2A, which is critical for its recruitment to target gene promoters like HOXA9 and MEIS1, driving oncogenic gene expression [PubMed 36823301]. While the mRNA itself represents a specific biomarker for diagnosis and minimal residual disease monitoring, therapeutic efforts largely target the resulting fusion protein or its essential co-factors. Current clinical developments include Menin-KMT2A inhibitors, such as revumenib and ziftomenib, which disrupt the interaction between Menin and the KMT2A fusion protein to induce myeloid differentiation and apoptosis in leukemic cells [PubMed 37612440]. Additionally, the mRNA sequence itself is a potential target for emerging RNA-based therapeutics such as antisense oligonucleotides or siRNA, aimed at degrading the oncogenic transcript before translation [PubMed 21633165].

Other names

MLL-AF6MLL-AFDNKMT2A-AF6t(6;11)(q27;q23) fusion

Small molecule inhibition of the Menin-KMT2A interaction to displace the fusion protein from chromatin; Inhibition of the histone methyltransferase DOT1L to reverse aberrant H3K79 methylation [PubMed 36823301, PubMed 25135958]