Menin–Mixed-lineage leukemia 1 (MLL1) protein–protein interaction (Menin–MLL1 PPI)

The Menin–Mixed-lineage leukemia 1 (MLL1) protein–protein interaction is a critical epigenetic and transcriptional regulatory mechanism that has emerged as a high-priority therapeutic target in hematologic malignancies [1, 2]. Menin, a scaffold protein encoded by the MEN1 gene, binds to the N-terminus of the MLL1 (also known as KMT2A) protein or its oncogenic fusion products [2, 3]. This interaction is essential for the recruitment of the MLL1 methyltransferase complex to specific chromatin loci, where it promotes the expression of homeobox genes such as HOXA9 and the transcription factor MEIS1 [6, 8]. In leukemias characterized by MLL1 rearrangements (MLL-r) or NPM1 mutations, this pathway is constitutively active, driving an undifferentiated, proliferative state in hematopoietic cells [6, 7]. Small molecule inhibitors designed to disrupt this interaction effectively "evict" the MLL1 complex from target promoters, leading to the downregulation of leukemogenic genes and the induction of terminal myeloid differentiation [6, 12]. Clinical candidates like revumenib and ziftomenib have demonstrated significant efficacy in relapsed or refractory acute leukemias, though challenges such as differentiation syndrome and the development of resistance mutations in the MEN1 binding pocket remain areas of active investigation [7, 10, 11].

Other names

Menin–KMT2A interactionMenin–MLL interactionMenin–MLL1 complexMEN1–KMT2A interaction

Disruption of the interaction between Menin and the N-terminus of MLL1 (or MLL fusion proteins), preventing the recruitment of the MLL complex to oncogenic target genes such as HOXA9 and MEIS1, which leads to the downregulation of these genes and induces cell differentiation and apoptosis [6, 7, 12].