Targeting the Menin–KMT2A interaction in leukemia: Lessons learned and future directions

Abstract Chromosomal rearrangements involving the Mixed Lineage Leukemia gene ( MLL1 , KMT2A ) are defining a genetically distinct subset in about 10% of human acute leukemias. Translocations involving the KMT2A ‐locus at chromosome 11q23 are resulting in the formation of a chimeric oncogene, where the N‐terminal part of KMT2A is fused to a variety of translocation partners. The most frequently found fusion partners of KMT2A in acute leukemia are the C‐terminal parts of AFF1, MLLT3, MLLT1 and MLLT10. Unfortunately, the presence of an KMT2A‐rearrangements is associated with adverse outcomes in leukemia patients. Moreover, non‐rearranged KMT2A‐complexes have been demonstrated to be crucial for disease development and maintenance in NPM1‐mutated and NUP98‐rearranged leukemia, expanding the spectrum of genetic disease subtypes that are dependent on KMT2A . Recent advances in the development of targeted therapy strategies to disrupt the function of KMT2A‐complexes in leukemia have led to the establishment of Menin–KMT2A interaction inhibitors that effectively eradicate leukemia in preclinical model systems and show favorable tolerability and significant efficacy in early‐phase clinical trials. Indeed, one Menin inhibitor, Revumenib, was recently approved for the treatment of patients with relapsed or refractory KMT2A‐rearranged acute leukemia. However, single agent therapy can lead to resistance. In this Review article we summarize our current understanding about the biology of pathogenic KMT2A‐complex function in cancer, specifically leukemia, and give a systematic overview of lessons learned from recent clinical and preclinical studies using Menin inhibitors.