Menin Inhibition in Acute Myeloid Leukemia: Pathobiology, Progress and Promise

Acute myeloid leukemia (AML) is a highly aggressive malignancy defined by significant biological diversity and variable patient outcomes. A key subset of AML is driven by abnormalities that lead to the overexpression of the oncogenic transcription factors HOXA9 and MEIS1. These abnormalities include KMT2A (formerly MLL) rearrangements and NPM1 mutations, as well as other rare lesions such as NUP98 rearrangements. This review focuses on the biology of the KMT2A, NPM1, and HOX/MEIS1 pathways, dissecting their molecular mechanisms of leukemogenesis. A central theme is the role of the scaffolding protein menin in the epigenetic regulation of this pathway, which ultimately drives malignant transformation. Currently, the clinical landscape is being transformed by the emergence of menin inhibitors as promising therapeutic agents for AML harboring these specific genetic anomalies. We evaluate the latest data on various menin inhibitors—both as monotherapy and in combinations—emphasizing their efficacy and safety profiles. As new evidence continues to accumulate with recent drug approvals and ongoing randomized, phase 3 studies, menin inhibitors are rapidly becoming a component of the AML treatment paradigm for relapsed/refractory and likely newly diagnosed disease.