Scientists Discover How To “Switch Off” Cancer Genes for Good

A new study shows that targeting key epigenetic proteins may permanently switch off cancer genes.

Scientists at Monash University, working with Harvard University, report they have found a way to permanently ‘switch off’ genes that help cancers survive. If the approach holds up in further testing, it could point to a new style of treatment that works with shorter courses and fewer of the harsh side effects that often come with long, continuous cancer therapy.

The team described the work in Nature Cell Biology. Their focus is epigenetic therapy, which aims to change how genes behave rather than rewriting the genes themselves. You can think of epigenetics as the cell’s operating instructions for when to read a gene and when to keep it quiet. Cancer mutations can corrupt those instructions, locking dangerous growth programs in the “on” position.

That problem is especially acute in some aggressive forms of acute leukemia. In these cases, a genetic error takes over the cell’s usual gene control machinery, keeping cancer-promoting genes switched on around the clock.

Drugs designed to interfere with that hijacked control system already exist, but researchers have not fully understood what makes them effective or how to use them in the most durable way.

Targeting Menin and DOT1L

Omer Gilan, Senior Research Fellow at Monash University’s School of Translational Medicine and Australian Centre for Blood Diseases, led the team that traced a key part of the mechanism. They found that targeting the epigenetic proteins Menin or DOT1L can permanently ‘switch off’ cancer-causing genes in leukemia cells.

Menin and DOT1L are part of the molecular toolkit cells use to manage gene activity, including chemical signals that help sustain a gene program over time.

“We have potentially identified a new way to exploit cancer’s weaknesses,” Dr. Gilan said.

“But the most exciting part of this is that clinicians can harness our findings to improve response and reduce side effects for patients.

“Anyone who has watched someone they love go through cancer treatment will attest to how difficult it is, so making treatment easier to withstand and more effective is absolutely vital.”

Erasing Cancer’s “Memory”

Daniel Neville, a Monash PhD candidate and lead author of the Nature Cell Biology study, explained that the advance builds on the concept of cellular “memory” linked to the epigenetic protein DOT1L in cancer cells.

“The drugs we use to target Menin erase the memory provided by DOT1L, and continue killing the cancer cells, even after the treatment has stopped,” he said.

“We hope that by reducing the treatment period, patients may tolerate higher doses or be eligible for additional therapies to improve outcomes.

“This is a big step forward for epigenetic therapy, and one we hope will change how cancer is treated more generally.”

Moving Toward Clinical Trials

The discovery is set to be tested in a clinical trial run by Monash University and The Alfred, later this year.

Associate Professor Shaun Fleming, clinical hematologist and head of the myeloid disease program at The Alfred and a researcher at Monash’s Australian Centre for Blood Diseases, says this is an exciting step forward for leukemia treatment.

“As we continue clinical trials of Menin inhibitors, and particularly moving into combination studies, understanding better how these new therapies work may allow us to utilize them more effectively and with a greater degree of safety in the future,” Associate Professor Fleming said.

Reference: “DOT1L provides transcriptional memory through PRC1.1 antagonism” by Daniel Neville, Daniel T. Ferguson, Emily B. Heikamp, Zhihao Lai, Graham W. Magor, Charlene Lam, Olivia G. Dobbs, Vita Levina, Kathy Knezevic, James J. The, Shania Alex, Stephen C. Suits, Bradon Rumler, Michael Uckelmann, Laure Talarmain, Enid Y. N. Lam, Andrew C. Perkins, Scott A. Armstrong, Charles C. Bell, Chen Davidovich and Omer Gilan, 3 February 2026, Nature Cell Biology.
DOI: 10.1038/s41556-025-01859-8

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