Targeting menin: a promising therapeutic strategy for susceptible acute leukemia subtypes
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Philipps-Universität Marburg
Abstract
Two recent studies published in Nature focused on the clinical efficacy of the menin inhibitor revumenib (SNDX-5613) in KMT2A (histone-lysine N-methyltransferase 2A)-rearranged or NPM1 (Nucleophosmin1)-mutant acute myeloid leukemia.1,2 These studies indicate that menin inhibition and its acquired resistance to long-term exposure to revuminib are key points for future treatment, emphasizing the role of menin as a challenging and promising target for the current treatment of leukemia.
KMT2A mutations arise in 80% of acute lymphoblastic leukemia (ALL) and, together with mutations related to NPM1, in 30% of acute myeloid, lymphoid or mixed phenotype leukemia (AML). KMT2A is a fine epigenetic regulator that binds the promoter sequences of the HOX (Homeobox) genes deputed for the proliferation of the lymphoblastic cells. These genes are normally not expressed in differentiated cells. Mutations occurring KMT2A cause the stabilization of the binding with menin, which is co-binding the promoter regions of the HOX. Thus triggering the transcription of the HOX genes and their DNA-binding-cofactor MEIS1 (Homeobox Protein Meis1), the uncontrolled proliferation and the further leukemic transformation. Besides, in AML with mutated NPM1, the KMT2A-menin synergy prompts HOX and MEIS1-mediated transcription of leukemia associated genes.