A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia

Abstract

Menin inhibitors are new and promising agents currently in clinical development that target the HOX/MEIS1 transcriptional program which is critical for leukemogenesis in histone-lysine N-methyltransferase 2A-rearranged (KMT2Ar) and in NPM1-mutated (NPM1mut) acute leukemias. The mechanism of action of this new class of agents is based on the disruption of the menin-KMT2A complex (consisting of chromatin remodeling proteins), leading to the differentiation and apoptosis of AML cells expressing KMT2A or with mutated NPM1. To date, this new class of drugs has been tested in phase I and II clinical trials, both alone and in combination with synergistic drugs showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this brief review, we summarize the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data on the treatment of acute myeloid leukemia with this promising new class of agents, particularly revumenib and ziftomenib.

Keywords: HOX genes; KMT2A; NPM1; acute leukemia; menin; menin inhibitors; revumenib; ziftomenib.

Figure 1

Cofactor menin is necessary for KMT2A to bind HOX gene promoters. In detail, KMT2A binding menin acts as a transcriptional upregulator of HOX genes and their cofactor MEIS1 (A). Disruption of this chromatin complex (by binding of the menin inhibitors and menin protein) leads to inhibition of the leukemogenic transcription program (downregulation of HOX genes) without affecting normal hematopoiesis (B).