Menin–MLL fusion protein interface

The **Menin–MLL fusion protein interface** is a critical protein–protein interaction between menin—a tumor suppressor encoded by the MEN1 gene—and the N-terminal region of MLL (KMT2A) fusion proteins generated by chromosomal translocations. This interface is **essential for the oncogenic activity of MLL fusion proteins in acute leukemias**, as it allows recruitment of MLL fusion complexes to target gene promoters (notably HOXA9 and MEIS1), driving aberrant gene expression and sustaining an undifferentiated, proliferative leukemic phenotype[1][2][3][4][6]. Drugs that disrupt this interface abrogate the leukemogenic program, and multiple classes of small molecule inhibitors (e.g., MI-2, MI-2-2, MIV-3, DSP-5336) are in development as **precision therapies for MLL-rearranged leukemias**[5][7]. This target is considered **highly druggable** by PPI inhibitors, and its blockade disrupts the menin-mediated scaffold essential for MLL fusion–driven epigenetic gene activation. Targeting the menin–MLL interface represents a promising therapeutic strategy for poor-prognosis leukemias driven by MLL rearrangements.

Other names

Menin–MLL interactionMenin–KMT2A fusion protein interfaceMEN1–MLL fusion protein interfaceMenin–MLL PPI (protein–protein interaction)

Inhibition of the menin–MLL protein–protein interaction with small molecules disrupts the ability of MLL fusion proteins to upregulate leukemogenic genes, leading to differentiation, apoptosis, and impaired proliferation of leukemic cells[4][3][5][6][7]. Mimicry of critical MLL residues or structural motifs by small molecules to competitively block menin binding[5]. These inhibitors block the assembly of the menin–MLL–LEDGF complex, essential for MLL fusion-driven transformation[2][7].