Menin is a protein in human cells, encoded by the MEN1 gene. It is present in the nucleus of many different cell types and appears active throughout all stages of development. Menin functions as a scaffold protein, meaning it brings other proteins together to regulate various cellular processes. This allows menin to influence gene expression and interact with multiple signaling pathways, underscoring its broad importance.
Menin’s Role in Healthy Cells
In healthy cells, menin plays several roles, including regulating gene expression, cell growth, differentiation, and DNA repair. It acts as a tumor suppressor, preventing uncontrolled cell growth and division. Menin achieves this by recruiting specific protein complexes, such as those containing Mixed Lineage Leukemia (MLL) proteins (MLL1 and MLL2), to gene promoters.
This recruitment regulates gene transcription. For instance, in endocrine cells, menin helps activate the transcription of antiproliferative genes, such as those for cyclin-dependent kinase (CDK) inhibitors like p18 and p27. By promoting these inhibitors, menin contributes to cell cycle control and prevents unregulated cell proliferation. Menin also contributes to DNA repair through interactions with proteins like checkpoint suppressor 1 (CHES1) and its localization to telomeres during meiosis, maintaining genomic stability.
Menin’s Link to Disease
Mutations or dysregulation of the MEN1 gene are directly linked to several diseases, particularly cancers. The most well-known is Multiple Endocrine Neoplasia type 1 (MEN1) syndrome, a rare hereditary disorder. This syndrome predisposes individuals to develop tumors in various endocrine glands, including the parathyroid, pituitary, and pancreas.
Hyperparathyroidism is the most common manifestation of MEN1, occurring in nearly all patients by age 50. Pancreatic islet cell tumors affect approximately 60% of individuals with MEN1. Pituitary gland tumors are also common. These tumors, even if benign, can lead to overproduction of hormones.
Beyond MEN1 syndrome, menin has a role in other cancers, acting as either a tumor suppressor or an oncogene. In specific leukemias, such as MLL-rearranged (MLL-r) leukemias, menin acts as an oncogenic cofactor. MLL-r leukemias are characterized by translocations of the MLL gene, which result in fusion proteins that interact with menin. This interaction drives the expression of specific genes, leading to uncontrolled proliferation of leukemic cells.
Disrupting its interaction with MLL fusion proteins can abolish their cancer-causing effects. Menin also influences other cancers, including hepatocellular carcinoma, prostate, breast, and Ewing’s sarcoma, where it contributes to tumor development.
Menin as a Therapeutic Target
Menin’s role in disease has led to its emergence as a therapeutic target. In leukemias driven by MLL rearrangements or NPM1 mutations, menin’s interaction with the MLL1 protein is important for the disease’s progression. This interaction drives the expression of genes that promote leukemia cell growth and prevent their normal differentiation.
Small molecule menin-MLL inhibitors are being developed to disrupt this aberrant interaction. These inhibitors bind directly to menin, preventing it from associating with MLL1 fusion proteins. By blocking this binding, the inhibitors can shut down the pro-leukemic gene expression pathway, leading to differentiation and apoptosis of leukemic cells.
Several menin inhibitors, such as revumenib (SNDX-5613) and ziftomenib (KO-539), have entered early-phase clinical trials for relapsed/refractory acute leukemias. Initial data show promising safety and efficacy, with some patients achieving complete remissions. This new class of drugs represents a distinct approach to cancer therapy, focusing on rehabilitating abnormal cells rather than directly killing them.