Histone-lysine N-methyltransferase 2A-FK506-binding protein fusion (MLL-FKBP) (MLL-FKBP)

MLL-FKBP is a synthetic fusion protein consisting of the N-terminal fragment of the Histone-lysine N-methyltransferase 2A (KMT2A, formerly MLL) fused to one or more FK506-binding protein (FKBP12) domains. While not a naturally occurring mutation, it serves as a critical therapeutic model and target in chemical biology for studying MLL-rearranged leukemias. In this system, the addition of a small-molecule dimerizer (such as AP20187) induces the dimerization of the MLL fragments, which effectively mimics the behavior of oncogenic MLL-fusion proteins (e.g., MLL-AF9 or MLL-AF4) by recruiting the DOT1L complex and activating HOX gene clusters. This model is extensively used to validate drugs that target the MLL complex, particularly Menin-MLL inhibitors like Revumenib, which prevent the fusion protein from binding to its essential cofactor, Menin. By disrupting this interaction, these drugs can reverse the leukemogenic gene expression program and induce cell cycle arrest or differentiation in malignant cells.

Other names

KMT2A-FKBP12 fusionMLL-FKBP12Conditional MLL fusion protein

Small-molecule chemical inducers of dimerization (CIDs) like AP20187 trigger the dimerization of the MLL-FKBP fusion, mimicking the constitutive activation of oncogenic MLL fusions. Conversely, Menin-MLL inhibitors disrupt the interaction between the MLL N-terminus and Menin, which is required for the stability and transcriptional activity of the complex.