Menin-Lysine methyltransferase 2A interface (Menin-KMT2A interface) (Menin-KMT2A)

Menin is a nuclear scaffold protein encoded by the MEN1 gene that plays a dual role in human health, acting as a tumor suppressor in endocrine tissues and an oncogenic cofactor in certain leukemias [6, 15, 16]. It functions by interacting with various proteins, most notably the histone methyltransferase Lysine methyltransferase 2A (KMT2A, also known as MLL1), to regulate the transcription of genes essential for hematopoiesis and embryonic development [1, 11, 17]. In acute leukemias harboring KMT2A rearrangements or NPM1 mutations, the Menin-KMT2A interaction becomes critical for the expression of leukemogenic genes such as HOXA9 and MEIS1, which block cellular differentiation and drive malignant proliferation [1, 11, 18]. Therapeutic targeting of the Menin-KMT2A interface with small-molecule inhibitors, such as revumenib and ziftomenib, disrupts this interaction and displaces the oncogenic complex from chromatin [2, 5, 15]. This action leads to the downregulation of the HOX/MEIS1 transcriptional program, inducing the differentiation and apoptosis of leukemic blasts [11, 13, 18]. While clinically promising, challenges include the management of differentiation syndrome and QTc prolongation, as well as the emergence of resistance mutations in the MEN1 binding pocket [5, 12, 15]. Ongoing research is also exploring the role of Menin inhibition in other conditions, such as diabetes and multiple myeloma, where it may influence beta-cell regeneration or MYC-driven signaling [8].

Other names

Menin-MLL1 interfaceMenin-Mixed lineage leukemia 1 interfaceMEN1-KMT2A interactionMenin-KMT2A complexMenin-MLL interface

Small-molecule inhibitors bind to the Menin protein at the KMT2A binding pocket, disrupting the protein-protein interaction and preventing the assembly of the oncogenic KMT2A fusion complex on chromatin, which downregulates leukemogenic genes like HOXA9 and MEIS1 and induces myeloid differentiation.