Written by: Dana-Farber Editorial Team
Medically Reviewed By: Scott Armstrong, MD, PhD, and Matthew Meyerson, MD, PhD
Menin, a protein located in the nucleus of various human cell types, often functions as a tumor suppressor by inhibiting excessive cell growth and division. It facilitates a complex of proteins involved in a cellular process called histone methylation, where chemical units called methyl groups are added to histone proteins that anchor DNA, thereby activating genes that control cell division.
If a mutation in the menin gene leaves it in any way defective or absent, histone methylation is disrupted and uncontrolled cell growth begins — cell growth that could lay the foundations for cancer.
Despite its properties as a guard over cell growth and cancer, menin presented itself as a contradiction to researchers like Matthew Meyerson, MD, PhD, director of Dana-Farber’s Center for Cancer Genomics, who helped identify an unexpected role for menin.
Meyerson’s laboratory first identified that menin, a protein of previously unknown function, worked by cooperating with MLL family proteins that methylate histones. Then, working collaboratively with researchers at Stanford, Meyerson’s research group studied a specific form of acute myeloid leukemia (AML) — one of the most difficult forms of leukemia to treat — which has mutations in KMT2A that create an abnormal form of the MLL protein, that turns normal white blood cells into leukemia cells. The Stanford researchers and the Meyerson laboratory showed that menin facilitates the growth of these KMT2A mutant leukemia cells — in fact is required for their growth–as opposed to stopping it.
In some types of acute myeloid leukemia (AML) cells, the abnormal MLL protein joins with the menin protein to activate genes that promote leukemia. Drugs that keep MLL and menin apart hinder those genes from being switched on.
Discovering that menin is a cancer-driving protein in leukemia meant researchers needed to find a small molecule drug to hinder the protein’s actions, therefore hindering the cancer’s growth. Research by Scott Armstrong, MD, PhD, senior vice president for drug discovery and chief research strategy officer at Dana-Farber, has been studying MLL-driven leukemias for over 20 years. His group found that disrupting the interaction of menin with MLL in multiple types of AML dependent on the MLL protein caused those cells to lose their cancerous qualities. Inhibiting menin — through creation of a menin inhibitor — meant a potential broad new approach to AML therapy.
In 2019, the Armstrong lab, working collaboratively with Syndax Pharmaceuticals, described a class of menin inhibitors that could eradicate leukemia in preclinical studies. This work prompted the clinical testing of the most advanced menin inhibitor of the class called revumenib. Recent clinical trials at Dana-Farber and throughout the United States demonstrated revumenib, a pill taken by mouth had minimal side effects and the power to help patients with advanced AML reach remission.
In November 2024, the U.S. Food and Drug Administration (FDA) approved revumenib for adults and children aged 1 year and older with relapsed or refractory AML with the KMT2A mutation. This is the first FDA approval of a menin inhibitor — a groundbreaking approval that not only helps patients with poor prognoses, but also sets the stage for protein inhibitors that may be applicable to a wide range of cancers.
Institute researchers in Armstrong’s lab continue to investigate menin inhibitors, tackling the potential issue of drug resistance. They have already uncovered insights that could lead to future solutions, including developing new drug molecules that deprive menin of any potential to bind MLL or combining menin inhibitors with drugs that use a different mechanism for keeping MLL and menin apart.