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

KMT2A-MLLT3 (also known as MLL-AF9) is a chimeric fusion protein resulting from the t(9;11)(p22;q23) chromosomal translocation, which is the most common KMT2A rearrangement in acute myeloid leukemia (AML) (viamedica.pl, nih.gov). This fusion protein is formed by the N-terminus of the Lysine methyltransferase 2A (KMT2A) and the C-terminus of MLLT3 (AF9) (oncokb.org). It functions as a potent oncogenic driver by constitutively activating a leukemogenic gene expression program, notably the upregulation of HOXA9 and MEIS1, which are master regulators of hematopoietic stem cell self-renewal (mdpi.com, frontiersin.org). The fusion protein achieves this by recruiting the Super Elongation Complex (SEC) and the histone methyltransferase DOT1L to target gene promoters, leading to aberrant H3K79 methylation and sustained transcriptional elongation (nih.gov, oncokb.org). Therapeutic targeting of KMT2A-MLLT3 primarily involves disrupting its interaction with the scaffold protein Menin or inhibiting the enzymatic activity of DOT1L (mdpi.com, cellsignal.com). Menin inhibitors, such as the FDA-approved revumenib and the investigational ziftomenib, have demonstrated significant clinical efficacy in inducing differentiation and achieving remissions in patients with KMT2A-rearranged leukemias (nih.gov, primeinc.org).

Other names

MLL-AF9KMT2A-AF9t(9;11) fusion proteinMLL/AF9 fusion proteinMLLT3-KMT2A

Inhibition of the Menin-KMT2A interaction to disrupt the recruitment of the fusion complex to chromatin, and inhibition of DOT1L methyltransferase activity to reduce aberrant H3K79 methylation.