Lysine methyltransferase 2A-MLLT3 fusion mRNA (KMT2A-MLLT3)

The KMT2A::MLLT3 fusion mRNA is an oncogenic transcript resulting from the t(9;11)(p22;q23) chromosomal translocation, which fuses the Lysine Methyltransferase 2A (KMT2A) gene with the MLLT3 (AF9) gene (Meyer et al., 2023, Leukemia). This fusion is a primary driver of acute myeloid leukemia (AML), particularly in pediatric and young adult populations, where it promotes the aberrant self-renewal of hematopoietic progenitor cells (Krivtsov & Armstrong, 2007, Nature Reviews Cancer). The resulting fusion protein acts as a chimeric transcription factor that constitutively activates downstream targets such as HOXA9 and MEIS1 by recruiting the Super Elongation Complex and the histone methyltransferase DOT1L (Yokoyama et al., 2005, Cell). While the mRNA itself serves as a critical diagnostic and minimal residual disease (MRD) biomarker, the protein product is the primary focus of therapeutic intervention. Current drug development strategies focus on disrupting the interaction between the KMT2A fusion protein and its essential cofactor, Menin, using small molecules like revumenib (Issa et al., 2023, Nature). Other approaches include the inhibition of DOT1L to reverse aberrant H3K79 methylation patterns induced by the fusion complex (Stein et al., 2018, Blood). These targeted therapies aim to reverse the epigenetic dysregulation driven by the fusion and induce terminal differentiation of leukemic blasts.

Other names

MLL-AF9t(9;11) fusion transcriptKMT2A-AF9MLL-MLLT3KMT2A-MLLT3

Disruption of the Menin-KMT2A protein-protein interaction to prevent transcriptional complex assembly at leukemogenic target genes; inhibition of DOT1L-mediated H3K79 methylation to reverse epigenetic reprogramming.