Staying One Step Ahead

New insights into how leukemia escapes treatment are shaping smarter combination therapies

Ten years ago, Scott A. Armstrong, MD, PhD, and his colleagues were analyzing gene expression profiles of leukemia when they noticed something striking: Two very different forms of acute myeloid leukemia (AML) appeared to share a common molecular origin. At the center of that connection was a little-known protein called menin.

For years, Armstrong and others at Dana-Farber had been studying a rare but highly aggressive subtype of AML caused by abnormalities in a gene called KMT2A. In this form of the disease, menin acts like a co-conspirator: It binds to a rogue fusion protein and switches on genes that drive leukemia cells to grow. Block the connection, the researchers reasoned, and you could stop disease at its source.

That insight paved the way for the development of a new class of drugs known as menin inhibitors.

As that development was underway, Armstrong discovered that menin was playing a similar sidekick role in a far more common type of AML driven by mutations in a gene called NPM1. Unlike KMT2A-rearranged AML, which accounts for about 5-10% of adult cases, NPM1-mutated AML affects roughly 30% of adults with the disease. Armstrong realized that the drug he was developing for a rare subtype might, in fact, help up to 40% of patients with AML. 

"That expanded the potential patient pool from 1,000 to 2,000 patients per year up to 15,000 to 20,000," says Armstrong, senior vice president for drug discovery and chief research strategy officer at Dana-Farber.

Armstrong's "aha moment" is one of many milestones in menin research at Dana-Farber. From unraveling menin's unusual biology, to designing small molecules to block it, to bringing those inhibitors into clinical trials, Dana-Farber investigators have dramatically expanded treatment options for people with AML. But in many ways, the story of menin research at Dana-Farber is just beginning. 

As leukemia cells grow more adept at evading menin inhibitors, Armstrong has shifted his focus to understanding the biology of resistance. Those insights, in turn, are guiding the development of combination therapies and other strategies aimed at deepening responses, overcoming resistance, and preventing relapse.

The Role of Menin in AML

The story of menin at Dana-Farber began two decades ago.

In 2004, Matthew L. Meyerson, MD, PhD, and his colleagues were studying menin in endocrine tumors, where the protein appeared to behave like a classic tumor suppressor. Mice genetically engineered to lack the menin protein developed endocrine tumors.

But in leukemia, menin plays a different role, as discovered by Michael Cleary's lab at Stanford together with Meyerson's lab at Dana-Farber. In AML driven by KMT2A abnormalities, menin doesn't suppress cancer, it fuels it. When bound to an abnormal fusion protein called MLL, menin helps activate genes that instruct leukemia cells to divide uncontrollably. 

"It is really kind of paradoxical," says Meyerson, director of Dana-Farber's Center for Cancer Genomics. "You have a tumor suppressor protein that, if you lose it, you get endocrine cancers. But in leukemia, you need this same protein to get cancer."

The realization that leukemia cells depend on menin to survive sparked a race to design potential drug compounds capable of blocking that interaction. Working with Syndax Pharmaceuticals, Armstrong and his colleagues began searching for small molecules that could wedge into menin's notoriously large binding pocket, preventing it from attaching to the MLL fusion protein. 

In 2015, the team tested one of their menin inhibitors in mouse models of leukemia. The results were dramatic.

"We essentially cured the mice of their aggressive leukemia, which we had never seen before," Armstrong says. 

Around the same time, Armstrong's lab confirmed that menin was just as essential in NPM1-mutated AML as it was in KMT2A-rearranged AML, expanding the potential impact of menin inhibition far beyond what researchers had first imagined.

How AML Develops Resistance to Menin Inhibitors

By 2019, one of the most promising inhibitors to emerge from Syndax and Armstrong's lab was moving from the bench to the bedside. Syndax launched the AUGMENT-101 clinical trial to evaluate revumenib, taken orally twice a day, in adults and children one year and older with KMT2A-rearranged and NPM1-mutated AML.

Many of the patients, who had stopped responding to standard treatments, achieved complete remissions with revumenib. The impressive results led to FDA approvals of revumenib, first for KMT2A-rearranged AML in late 2024, then for NPM1-mutant disease in late 2025. Two decades of relentless research at Dana-Farber into menin and its connection to AML had come to fruition.

"Revumenib was the first drug that showed proof of principle that it would work as a single agent to treat these types of leukemias that had failed other treatments," says Richard M. Stone, MD, director of the Adult Acute Leukemia Program, who led Dana-Farber's participation in the trial. "However, not everybody will respond to these drugs."

With that challenge in mind, Armstrong and his colleagues turned their attention to understanding how leukemia cells develop resistance to menin inhibitors.  

"Leukemia cells divide and proliferate rapidly and are very good at generating mutations," Armstrong says. "What we found is that the leukemia mutates itself such that the small molecule can no longer bind to the menin protein. That happens both in KMT2A-rearranged leukemia and in NPM1-mutant leukemia."

Armstrong notes that roughly 40% of AML patients treated with revumenib will develop this type of resistance. Another form of resistance emerges from cancer cells that remain despite treatment with a menin inhibitor, known as measurable residual disease.

"We are in the process of understanding what is allowing those persistent cells to remain in the presence of the menin inhibitor, because ultimately that is where the resistance will come from," Armstrong says.

Such insights are guiding the development of new strategies to overcome resistance, such as combination therapies that target multiple vulnerabilities at the same time.  

Using Combination Therapy to Outmaneuver AML

Jacqueline S. Garcia, MD, a medical oncologist in the Adult Leukemia Program at Dana-Farber, and Stone are studying the effectiveness of combining menin inhibitors with other targeted therapies. 

"The next decade for menin inhibition is about how we partner these drugs to prevent or address resistance mechanisms," Garcia says.

Clinical trials are ongoing to evaluate combination therapies with approved menin inhibitors, revumenib and ziftomenib, as well as other inhibitors that are still under development, such as bleximenib and enzomenib. 

Stone notes that when a drug proves effective as a single agent in the advanced disease setting, the next step is to move it up in the course of treatment – that is, use it to treat patients with less advanced disease – where it may have a more profound effect before resistance can emerge.

For example, Stone is leading a phase 1 trial evaluating the combination of revumenib with chemotherapy and the multi-kinase inhibitor midostaurin for frontline treatment of NPM1- and FLT3-mutated AML. He notes that the results in newly diagnosed patients have been "very encouraging."

Garcia is leading a phase 3 trial evaluating a triplet regimen of bleximenib, azacitidine, and venetoclax in adults newly diagnosed with either KMT2A-rearranged or NPM1-mutated AML. She is also leading a phase 2 trial evaluating the combination of revumenib and venetoclax to simultaneously block menin and the BCL2 protein. The goal is to wipe out any remaining cancer cells in people with AML.

"We're studying all these scenarios to determine the best frontline combinations, the right combinations at the time of relapse, and how to prevent relapse in patients who are in remission," Garcia says.

Menin Inhibitors for Pediatric AML

Researchers at Dana-Farber are also working to expand treatment options for children with AML. Standard therapy typically includes intensive chemotherapy, sometimes followed by a stem cell transplant. But these treatments don't cure all patients and can carry significant long-term side effects.

Jessica A. Pollard, MD, clinical director of the Pediatric Hematologic Malignancy Center at at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, says menin inhibitors could offer a targeted approach for children with KMT2A-rearranged AML as well as NUP98-rearranged AML, a very high-risk subset that is rarer but, like KMT2A-rearranged disease, responds to menin inhibition. Taken orally, these drugs are often easier for children to tolerate and may cause fewer side effects than traditional chemotherapy. In some cases, they may even help children avoid a transplant altogether.

Unlike in adults, KMT2A rearrangements are relatively common in pediatric AML, making many children potential candidates for menin inhibitors. In the AUGMENT-101 trial, which included 13 pediatric patients with KMT2A-rearranged AML, 4 achieved complete remission with revumenib, and many had no detectable disease.

Pollard notes that enrolling both adults and children in trials like AUGMENT-101 accelerated the approval of drugs such as revumenib for pediatric patients. She is now developing a study through the Children's Oncology Group to evaluate menin inhibitors as part of frontline therapy for children with newly diagnosed KMT2A -rearranged or NUP98-rearranged AML. Her team is also exploring combination strategies for patients whose leukemia carries additional mutations, including FLT3 abnormalities.

As in adults, drug resistance can develop in pediatric patients, making the search for effective combination therapies equally urgent. 

"Even with multiple drugs being studied, we still can't always offer kids a clinical trial that entails menin inhibition," Pollard says. "That's why we believe in having a broader portfolio testing multiple agents."

What Comes Next in Menin Research

Meanwhile, Armstrong's lab continues to probe the biology of resistance. He and his colleagues have discovered that another protein, KAT6A, also plays a role in how leukemia cells respond to menin inhibitors, and small molecules are already being developed to target this protein. The combination of a KAT6A/B inhibitor and a menin inhibitor has shown promise in laboratory models. 

"When you treat with a KAT6A/B inhibitor and a menin inhibitor, it's much more effective than either one alone," Armstrong says.

The implications are already reaching beyond leukemia. Armstrong recently published findings showing that combining KAT6A/B inhibitors with menin inhibitors can slow the growth of estrogen receptor-positive breast cancers.

"I'm hopeful that what we're doing in leukemia might be able to be translated to other cancers," Armstrong says.

From bench to bedside and back again, the story of menin is just one example of the arc of discovery at Dana-Farber. Each clinical advance generates new questions in the laboratory. Each relapse helps investigators learn more about the biology of the disease.

While cancer cells continue evolving to sidestep drugs, Dana-Farber scientists are also adapting, gaining new insights to stay one step ahead.

By Linda Wang