Menin–KMT2A protein–protein interaction

The **menin–KMT2A protein–protein interaction** is a critical molecular complex formed between the scaffold protein menin (encoded by MEN1) and the histone methyltransferase KMT2A (also known as mixed-lineage leukemia 1, MLL1). Menin acts as a nuclear scaffold, facilitating the binding of KMT2A and its fusion proteins to chromatin, and is essential for recruiting additional chromatin regulators that drive the expression of specific gene sets, particularly HOXA cluster genes and MEIS1. This interaction is indispensable for the oncogenic transcriptional programs underlying KMT2A-rearranged (KMT2Ar) leukemias and NPM1-mutant AML, leading to uncontrolled cell proliferation and a block in normal hematopoietic differentiation. Pharmacological inhibition of the menin–KMT2A interaction is being actively explored as a therapeutic strategy, and multiple agents targeting this protein–protein interaction are in clinical or preclinical development. Resistance mutations in the menin protein can reduce drug efficacy and are being monitored in ongoing trials. This target represents a paradigm for indirect inhibition of oncogenic transcriptional complexes in cancer therapy.

Other names

Menin–MLL interactionMenin–KMT2A interactionMEN1–KMT2A interactionMenin–mixed lineage leukemia (MLL) fusion protein interaction

Allosteric inhibition of the menin–KMT2A interaction to prevent oncogenic gene expression (especially HOX/MEIS1 upregulation); Disruption of the chromatin complex to restore differentiation and block leukemogenesis; Epigenetic reprogramming via loss of aberrant methylation at target genes