Lysine methyltransferase 2A fusion protein (MLL fusion protein) (KMT2A-FP)

Lysine methyltransferase 2A (KMT2A) fusion protein, historically known as Mixed-lineage leukemia (MLL) fusion protein, is a potent oncogenic driver resulting from chromosomal translocations at the 11q23 locus (Kohlmann et al., 2008, JCO). These rearrangements fuse the N-terminal portion of the KMT2A gene with one of over 80 different partner genes, most commonly AF4, AF9, or ENL (Marschalek, 2011, Br J Haematol). The resulting chimeric protein loses its original histone H3K4 methyltransferase activity but gains the ability to constitutively recruit transcriptional co-activators like the Super Elongation Complex (SEC) and the histone methyltransferase DOT1L (Slany, 2009, Haematologica). This leads to the sustained overexpression of homeobox genes, such as HOXA9 and MEIS1, which arrests hematopoietic development and drives the progression of aggressive acute leukemias (Krivtsov & Armstrong, 2007, Nat Rev Cancer). Therapeutic targeting focuses on disrupting the essential interaction between the MLL fusion protein and its cofactor Menin, or inhibiting downstream epigenetic modifiers like DOT1L to restore normal cellular differentiation (Issa et al., 2023, Nature). Clinical development of Menin-KMT2A inhibitors has shown significant promise, particularly in patients with relapsed or refractory MLL-rearranged leukemias, by inducing complete remissions through a differentiation-based mechanism (Stein et al., 2023, JCO). However, challenges such as the development of resistance mutations in the Menin-binding pocket and the management of differentiation syndrome remain key areas of investigation (Perner et al., 2023, Nature).

Other names

Mixed-lineage leukemia fusion proteinKMT2A rearrangementMLL-rearranged proteinHRX fusion proteinALL-1 fusion protein

Disruption of the protein-protein interaction between the N-terminus of the MLL fusion protein and the scaffold protein Menin (Issa et al., 2023, Nature); inhibition of the histone methyltransferase DOT1L to prevent H3K79 methylation (Daigle et al., 2011, Cancer Cell); disruption of the Super Elongation Complex (SEC) recruitment (Lin et al., 2010, Cell).