Menin–Lysine Methyltransferase 2A (KMT2A) complex and Fms-like tyrosine kinase 3 (FLT3) (Menin-KMT2A/FLT3)

The Menin-KMT2A complex and Fms-like tyrosine kinase 3 (FLT3) represent a critical therapeutic axis in the treatment of acute leukemias, particularly Acute Myeloid Leukemia (AML). Menin is a scaffold protein that binds to the N-terminus of Lysine Methyltransferase 2A (KMT2A), an interaction essential for maintaining the expression of leukemogenic genes like HOXA9 and MEIS1 (Issa et al., Nature, 2023). FLT3 is a receptor tyrosine kinase that, when mutated through internal tandem duplications (ITD), drives uncontrolled cell proliferation and is associated with poor prognosis (Perl et al., NEJM, 2019). In many cases of AML, these two pathways are co-activated, and preclinical studies have shown that Menin inhibition can sensitize leukemic cells to FLT3 inhibitors (Dzama et al., Blood, 2020). Therapeutic targeting involves small molecules that disrupt the Menin-KMT2A protein-protein interaction and inhibitors that block FLT3 kinase activity. Clinical trials, such as the SAVE trial (NCT05394545), are currently evaluating the combination of Menin inhibitors like revumenib with FLT3 inhibitors like gilteritinib to achieve synergistic anti-leukemic effects. This dual-targeting strategy is particularly relevant for patients with KMT2A-rearranged or NPM1-mutated AML who also harbor FLT3 mutations. By simultaneously addressing epigenetic dysregulation and proliferative signaling, this approach aims to overcome clonal heterogeneity and improve patient outcomes in refractory settings.

Other names

MLL1MEN1CD135FLK2STK1Fms-related receptor tyrosine kinase 3MLL-rNPM1-mutant AML

Inhibition of the protein-protein interaction between Menin and KMT2A to disrupt oncogenic gene expression, combined with the inhibition of FLT3 receptor tyrosine kinase activity to block proliferative signaling pathways.