Targeting menin in lysine methyltransferase 2A/nucleophosmin-mutated leukemia: A novel strategy from epigenetic dysregulation to clinical therapy (Review).

Menin protein is encoded by the multiple endocrine neoplasia type 1 gene, which typically serves an oncogenic role in endocrine organs. However, in mice, menin protein is a key mediator of leukemic transformation, particularly in acute myeloid leukemia (AML), and is involved in the disease process through epigenetic regulatory mechanisms. This functional paradox may be due to the unique gene expression regulatory properties of menin, which can both activate and inhibit the expression of target genes. At the molecular level, menin protein regulates the gene transcription process by interacting with multiple protein complexes and forms a complex network with multiple signaling pathways. As the core hub of transcriptional regulation, menin protein is essential for the maintenance of cellular homeostasis and its aberrant function can lead to gene expression disorders, which contributes to the development of AML. Despite the druggability challenges of several transcriptionally regulated proteins, inhibitors of menin protein have made breakthroughs in clinical development. Particularly in AML subtypes [for example, lysine methyltransferase 2A (KMT2A) rearrangement or nucleophosmin (NPM1) mutation], menin protein inhibitors have demonstrated favorable efficacy. The present study systematically reviewed biological functions of the menin protein and its application in targeted therapy for specific AML subtypes. Notably, menin inhibitors have demonstrated potential in KMT2A/NPM1-mutant leukemia, however, the off-target effects, resistance mechanisms and a lack of biomarkers due to the extensive nature of their binding interface remains to be elucidated.