Menin-Lysine Methyltransferase 2A complex (Menin-MLL complex)

The Menin-Lysine Methyltransferase 2A (Menin-MLL/KMT2A) complex is a critical epigenetic regulatory assembly that controls gene expression during hematopoiesis (Yokoyama et al., 2005, Cell). Menin, a scaffold protein encoded by the MEN1 gene, binds to the N-terminus of the KMT2A (MLL1) protein, facilitating its recruitment to target gene promoters (Caslini et al., 2007, Cancer Research). In leukemias characterized by KMT2A rearrangements (KMT2Ar) or NPM1 mutations, this complex is hijacked to drive the constitutive expression of oncogenic transcription factors like HOXA9 and MEIS1 (Kuhns et al., 2020, Cancer Discovery). This aberrant gene expression prevents the differentiation of hematopoietic stem cells, leading to the proliferation of leukemic blasts (Issa et al., 2023, Nature). Therapeutic intervention focuses on small-molecule inhibitors, such as revumenib and ziftomenib, which disrupt the protein-protein interaction between Menin and KMT2A (Kura Oncology, 2023; Syndax Pharmaceuticals, 2023). These inhibitors induce clinical remissions by promoting myeloid differentiation and downregulating the leukemogenic program (Stein et al., 2023, ASH). Clinical trials have demonstrated significant efficacy in patients with relapsed or refractory acute leukemias, though challenges such as differentiation syndrome have been observed (Stein et al., 2023, ASH). Additionally, the emergence of resistance mutations within the Menin binding pocket of the MEN1 gene has been identified as a mechanism of escape (Perner et al., 2023, Nature). The development of this class of inhibitors represents a major shift toward precision medicine in treating genetically defined subsets of acute leukemia.

Other names

Menin-MLL1 complexMEN1-KMT2A complexMenin-Mixed Lineage Leukemia complex

Small-molecule inhibition of the protein-protein interaction between Menin and the N-terminal fragment of KMT2A (MLL1) (Issa et al., 2023, Nature)