The menin protein is a scaffolding protein found within cells throughout the body. It is encoded by the MEN1 gene. Menin brings other proteins together to regulate gene expression, which is important for cell growth, differentiation, and senescence. Its presence in the nucleus of many cell types and activity across all developmental stages show its significance in cellular function.
Normal Biological Functions of Menin
Menin participates in regulating gene transcription, influencing whether specific genes are turned on or off. This regulatory function is achieved by interacting with various protein partners, including transcription factors, which bind to specific DNA regions. By serving as a scaffold, menin helps assemble protein complexes that can either activate or repress gene expression.
The protein also impacts cell proliferation. Menin upregulates the expression of cyclin-dependent kinase (CDK) inhibitors like p18 and p27, which in turn reduce beta cell proliferation. This interaction involves MLL1, a protein that adds a specific modification to histone H3, leading to gene activation.
Beyond proliferation, menin is involved in cell differentiation. For instance, it influences the differentiation of mesenchymal stem cells into osteoblasts, cells that form bone. Inactivation of menin has been observed to hinder this commitment to the osteoblast lineage.
Menin also contributes to DNA repair mechanisms. It interacts with proteins involved in DNA replication and repair, such as checkpoint suppressor 1 (CHES1). Additionally, menin has been found to localize to telomeres during meiosis, suggesting a role in telomere maintenance.
Menin’s Involvement in Disease Development
When menin’s function is impaired, it can contribute to the development of various diseases, particularly certain cancers. The most well-established link is its role in Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome. This genetic disorder is caused by mutations in the MEN1 gene.
In MEN1 syndrome, menin acts as a tumor suppressor. Mutations in the MEN1 gene often lead to truncated or absent menin, preventing it from effectively suppressing uncontrolled cell growth. This impairment results in the formation of tumors in endocrine glands such as the parathyroid glands, pancreatic islets, and anterior pituitary gland. Hyperparathyroidism, characterized by overactivity of the parathyroid glands, is the most common feature of MEN1 syndrome, affecting around 95% of patients.
Beyond MEN1 syndrome, altered menin function has been implicated in other types of cancer, including certain leukemias. In these cases, menin can paradoxically act as an oncogenic co-factor, promoting cancer growth. For instance, in acute myeloid leukemia (AML) with MLL-rearrangements, menin interacts with MLL fusion proteins, leading to the activation of genes like HOXA9 and MEIS1, which drive leukemic cell proliferation. Preventing the binding of these MLL fusion proteins to menin has been shown to abolish their cancer-promoting effects in laboratory and animal studies.
Therapeutic Strategies Targeting Menin
One strategy involves the development of menin inhibitors, drugs designed to block the interaction between menin and its binding partners. These inhibitors are particularly relevant in treating certain leukemias, such as MLL-rearranged acute myeloid leukemia (AML) and AML with NPM1 mutations.
Menin inhibitors work by preventing the menin protein from interacting with the KMT2A (formerly MLL) complex. This disruption switches off the signaling pathway that drives the proliferation of leukemic cells, promoting their differentiation into more normal cells. Several small molecule menin inhibitors are currently undergoing clinical evaluation.
Examples of these inhibitors include SNDX-5613 (revumenib) and KO-539 (ziftomenib), which have shown encouraging efficacy and acceptable tolerability in early-phase clinical trials for patients with relapsed or refractory acute leukemia. Revumenib has demonstrated approximately 27% response rates in KMT2A-rearranged leukemias and about 30% in NPM1-mutated cases. Further research is ongoing to evaluate the safety and effectiveness of menin inhibitors in combination with existing standard-of-care treatments for a broader range of leukemias.