Menin Inhibitors: New Targeted Therapies for Specific Genetic Subtypes of Difficult-to-Treat Acute Leukemias

Abstract

Menin (MEN1) is a well-recognized powerful tumor promoter in acute leukemias (AL) with KMT2A rearrangements (KMT2Ar, also known as MLL) and mutant nucleophosmin 1 (NPM1m) acute myeloid leukemia (AML). MEN1 is essential for sustaining leukemic transformation due to its interaction with wild-type KMT2A and KMT2A fusion proteins, leading to the dysregulation of KMT2A target genes. MEN1 inhibitors (MIs), such as revumenib, ziftomenib, and other active small molecules, represent a promising new class of therapies currently under clinical development. By disrupting the MEN1-KMT2Ar complex, a group of proteins involved in chromatin remodeling, MIs induce apoptosis and differentiation AL expressing KMT2Ar or NPM1m AML. Phase I and II clinical trials have evaluated MIs as standalone treatments and combined them with other synergistic drugs, yielding promising results. These trials have demonstrated notable response rates with manageable toxicities. Among MIs, ziftomenib received orphan drug and breakthrough therapy designations from the European Medicines Agency in January 2024 and the Food and Drug Administration (FDA) in April 2024, respectively, for treating R/R patients with NPM1m AML. Additionally, in November 2024, the FDA approved revumenib for treating R/R patients with KMT2Ar-AL. This review focuses on the pathophysiology of MI-sensitive AL, primarily AML. It illustrates data from clinical trials and discusses the emergence of resistance mechanisms. In addition, we outline future directions for the use of MIs and emphasize the need for further research to fully realize the potential of these novel compounds, especially in the context of specific genetic subtypes of challenging AL.

Keywords: HOX; KMT2A; NPM1; acute myeloid leukemia; genomic mutations; menin; menin inhibitors; revumenib; targeted therapy; ziftomenib.

Figure 1

The critical role of MEN1 in regulating gene expression. MEN1 interacts with various transcription factors and chromatin regulators, particularly by binding to KMT2A. This binding site is conserved across all KMT2A fusion proteins and is an essential cofactor for interactions with HOX gene promoters. KMT2Ar leukemias are characterized by the abnormal overexpression of HOX genes and their cofactor, MEIS1. In contrast, NPM1m is primarily located in the cytoplasm and exhibits a gene expression profile that resembles that of KMT2Ar leukemias, featuring the upregulation of HOX genes. This results in a block of hematopoietic differentiation and contributes to leukemic transformation. Revumenib and ziftomenib are MEN1 inhibitors disrupting the chromatin complex between MEN1 and KMT2A. By inhibiting this interaction, these inhibitors target the abnormal transcriptional program linked to leukemogenesis and induce apoptosis without adversely affecting normal hematopoiesis [34]. Legend: KMT2A: Lysine Methyltransferase 2A; NPM1: Nucleophosmin 1; AML: Acute Myeloid Leukemia; HOX: Homeobox Gene Family; MEIS1: Meis Homeobox 1; SEC: Super Elongation Complex; DOT1L: DOT1-Like Histone Lysine Methyltransferase; LEDGF: Lens Epithelium-Derived Growth Factor (Taken and adapted with author’s permission from reference [34]).