70-Year-Old Leukemia Drug Gets Surprising New Insight

A team of researchers just solved a 70-year-old puzzle about how a common leukemia drug actually works in our bodies. Their discovery reveals a hidden mechanism that could explain why some patients respond better to treatment than others.

The drug 6-thioguanine has saved countless lives since doctors first used it to treat leukemia in the 1950s. Despite decades of use, scientists still didn't fully understand what made some cancer cells vulnerable to it while others resisted.

Researchers at CeMM Research Center in Austria and the University of Oxford discovered that a protein called NUDT5 plays a surprising role in how cells respond to the drug. What makes this finding unusual is that NUDT5 doesn't work the way scientists expected it to.

Most proteins in our cells act like tiny machines with specific jobs. Scientists thought NUDT5 influenced the drug through its normal enzymatic activity. When the team blocked that activity, nothing happened.

Then they tried something different. Instead of just blocking NUDT5, they removed it entirely from cells using a cutting-edge technique called targeted protein degradation. The results were striking: without NUDT5 present, cells became more resistant to the leukemia drug.

"We initially expected that NUDT5 would influence the drug through its enzymatic activity," said Tuan-Anh Nguyen, one of the study's lead authors. "Instead, we found that what mattered was whether the protein itself was present."

The discovery builds on earlier work from 2025 showing that NUDT5 acts more like a scaffold than an enzyme. It helps organize cellular processes just by being there, not by performing chemical reactions.

The team also found that NUDT5 works opposite to another protein called NUDT15, which doctors already knew affected patient responses to thiopurine drugs. While losing NUDT15 makes cells more sensitive to treatment, losing NUDT5 makes them more resistant.

The Bright Side

This breakthrough doesn't offer a new treatment just yet, but it opens doors that were previously invisible. Understanding why patients respond differently to this widely used drug could eventually help doctors personalize treatment plans for better outcomes.

The study, published in Nature Communications, demonstrates how new technologies can reveal hidden layers of biology in treatments we've used for generations. Sometimes the biggest discoveries come from taking a fresh look at what we thought we already understood.

For the thousands of leukemia patients who receive thiopurine drugs each year, this research represents real progress toward more effective, personalized cancer care.