Scientists at Zhejiang University School of Medicine have discovered a hidden genetic factor that explains why some leukaemia patients stop responding to arsenic-based therapy, which is generally effective. The discovery is based on a little mutation in a patient's DNA that discreetly inhibits the drug's efficacy, raising expectations for improved screening and early intervention.

Acute promyelocytic leukaemia (APL) is a rapidly developing kind of blood cancer. Most patients have found arsenic trioxide, a medication made from arsenic, to be extremely successful, particularly when paired with other therapies. However, a tiny number of people have cancer recurrence. Until today, doctors had no idea why these incidents happened.

"We have long been puzzled by why a small subset of patients still relapse despite arsenic trioxide's proven efficacy," said Professor Hua Naranmandura, the study's senior researcher. "This study finally uncovers a hidden genetic factor, bringing us closer to preventing those relapses." 

The discovery came when researchers studied a relapsed patient's DNA and discovered a minor change — known as the A216V mutation — in the normal version of the PML gene. This was surprising because most APL instances are driven by a defective gene, PML::RARα, rather than the normal one. Even while this fusion gene remained unaltered, the patient's cancer had reappeared. 

Lab tests showed that the altered normal PML protein behaved as a glue, binding more strongly to the PML::RARα fusion protein. This prevented arsenic trioxide from breaking down, which is required to destroy cancer cells. When scientists deleted a key "coiled" area from the mutant protein, it stopped interfering, and the medicine resumed working. This identifies a clear mechanism of resistance and suggests a potential solution. 

To confirm the findings, the researchers took a two-pronged method. They sequenced patient samples to examine both the normal and fusion variants of the PML gene. Then, they modified lab-grown cells to carry either the normal or mutant gene and subjected them to arsenic trioxide. They used enhanced imaging and protein assays to track how the medication affected cancer-causing proteins. This strategy provided strong and trustworthy evidence tying the mutation to treatment failure. 

This discovery has novel implications for public healthcare prevention and policy change. If unrearranged PML screening is included in routine tests, doctors can detect drug resistance early and suggest other treatments before a recurrence occurs. 

"We hope that adding unrearranged PML screening into standard panels will become routine," said Professor Naranmandura. "Early identification of at-risk patients means we can tailor therapy before resistance emerges, ultimately improving survival and reducing costs." 

The findings also point to new avenues for test producers and health officials to enhance cancer treatment guidelines, increasing patient outcomes and lowering economic burdens.