Menin–MLL histone methyltransferase complex

The term “Menin–MLL2 complex” refers to a **protein–protein interaction within the larger MLL1/MLL2 COMPASS-like histone methyltransferase complexes**, rather than a stand‑alone, uniquely defined receptor or enzyme. Menin is an ubiquitously expressed nuclear protein that binds the N‑termini of **MLL1 (KMT2A)** and **MLL2 (KMT2B)**, which are SET‑domain lysine methyltransferases that catalyze histone H3 lysine 4 (H3K4) methylation in large multi‑subunit complexes containing core WRAD subunits (WDR5, RbBP5, ASH2L, DPY30) and other cofactors[1][2]. Menin is a common, near‑stoichiometric component of wild‑type MLL1 and MLL2 complexes and is required for their transcriptional activity, facilitating recruitment to target genes and maintenance of H3K4me3 at promoters of bivalent developmental genes and HOX/MEIS1 loci[1][2][3]. The **menin–MLL interaction pocket** on menin recognizes short N‑terminal menin‑binding motifs (MBM1, MBM2) from MLL1/MLL2, and crystal structures show that small‑molecule inhibitors such as **MI‑2 and MI‑2‑2** bind in this pocket, closely mimicking key contacts of the MLL MBM1 peptide and thereby competitively inhibiting the menin–MLL interaction[2]. Disruption of this interaction preferentially impairs leukemogenic MLL fusion protein complexes (MLL‑FPs), which are highly dependent on menin to bridge binding to chromatin (via LEDGF and other partners), and thus the **menin–MLL complex is considered a validated therapeutic epigenetic target** in MLL‑rearranged leukemias[2][3].

Other names

Menin–KMT2A/MLL1 complexMenin–KMT2B/MLL2 complexMenin–MLL interactionMenin–MLL1/MLL2 complexMenin–Trithorax (Trx) complex

Small-molecule inhibitors bind to the central pocket of menin, competitively blocking the high‑affinity menin‑binding motif (MBM1) of MLL1/MLL2, thereby disrupting the menin–MLL protein–protein interaction, dislodging MLL complexes from target genes, and downregulating oncogenic transcription programs such as HOX/MEIS1 in MLL‑rearranged leukemias[2][3].