Menin–Lysine methyltransferase 2A complex (Menin–KMT2A)

The Menin–Lysine methyltransferase 2A (KMT2A) complex is a critical epigenetic regulatory assembly composed of the scaffold protein menin (encoded by the MEN1 gene) and the histone methyltransferase KMT2A (also known as MLL1). In healthy cells, this complex regulates the transcription of genes essential for normal hematopoiesis and embryonic development, such as the HOX gene clusters. However, in specific subsets of acute leukemia, including those with KMT2A rearrangements (KMT2Ar) or NPM1 mutations (NPM1m), the interaction between menin and KMT2A becomes a central driver of oncogenesis. The complex tethers leukemogenic fusion proteins to chromatin, leading to the constitutive overexpression of HOXA9 and MEIS1, which blocks myeloid differentiation and promotes uncontrolled cell proliferation. Therapeutic targeting of this complex involves small-molecule inhibitors that disrupt the protein-protein interaction between menin and KMT2A. This disruption results in the downregulation of the leukemic gene expression program, inducing differentiation and apoptosis of the malignant cells. Clinical candidates like revumenib and ziftomenib have shown significant efficacy in relapsed or refractory acute leukemias, with revumenib receiving FDA approval for these indications.

Other names

Menin–MLL complexMenin–MLL1 complexMenin–Lysine methyltransferase 2A complexMenin–KMT2A interaction

Disruption of the protein-protein interaction between menin and KMT2A (or KMT2A-fusion proteins), preventing the anchoring of the KMT2A complex to chromatin and leading to the downregulation of leukemogenic genes such as HOXA9 and MEIS1.