(Press-News.org)
Researchers at Zhejiang University School of Medicine have identified a single point mutation in the normal PML gene that can block the effect of arsenic trioxide, a frontline drug for acute promyelocytic leukemia. This discovery uncovers a hidden cause of treatment failure and suggests a new target for genetic screening in relapsed patients. This work addresses the urgent issue of why some patients relapse despite a therapy that otherwise greatly improves survival.
Mutation Explains Why a Small Portion of Leukemia Patients Relapse on Arsenic Therapy
Arsenic trioxide cures most acute promyelocytic leukemia patients, but some patients relapse without an apparent genetic reason. Discovering that mutations in the intact PML allele confer resistance offers a way to predict and prevent treatment failure. Clinicians could add this test to standard panels to guide personalized therapy. For diagnostic developers, it points to the development of new assays. Healthcare policymakers can update screening guidelines to reduce relapse costs and improve patient outcomes. The finding also advances scientific understanding of how normal and fusion proteins interact under treatment.
“We have long been puzzled by why a small subset of patients still relapse despite arsenic trioxide’s proven efficacy,” says Prof. Hua Naranmandura. “This study finally uncovers a hidden genetic factor, bringing us closer to preventing those relapses.”
A216V Change in Healthy PML Locks On Fusion Protein, Revealing New Drug-Resistance Switch
The researchers identified an A216V mutation in the unrearranged PML gene of a relapsed patient, while the PML::RARα fusion gene remained unmutated. Cells carrying this mutation failed to degrade the disease-driving fusion protein when treated with arsenic trioxide, indicating resistance to the treatment. Laboratory models demonstrated that the mutant PML binds more tightly to the PML::RARα protein, thereby preventing the drug-induced destabilization of this complex. Importantly, deleting the coiled-coil region of the mutant PML abolished this abnormal interaction and restored drug sensitivity, pinpointing a mechanism for resistance and a possible intervention point.
Patient Sequencing and Engineered Cells Spotlight How Mutant PML Thwarts Arsenic-Induced Breakdown
The team sequenced bothPML and PML::RARα genes from patient samples and compared the arsenic sensitivity of PML::RARα fusion protein to those in standard cell lines. They then engineered laboratory cells to carry either the standard or mutant versions of PML, treated them with arsenic trioxide, and used protein assays and high-resolution microscopy to track the effects of the drug on the leukemia-driving fusion protein. This combination of patient data and controlled cell experiments ensured robust, clinically relevant results.
“We hope that adding unrearranged PML screening into standard panels will become routine,” says Prof. Hua Naranmandura. “Early identification of at-risk patients means we can tailor therapy before resistance emerges, ultimately improving survival and reducing costs.”
Published in Research in May 2025, this study shows that testing the unrearranged PML allele is crucial for understanding and overcoming arsenic trioxide resistance in acute promyelocytic leukemia. Incorporating screening for such mutations into clinical practice could lead to more effective and more personalized treatment strategies for patients at risk of relapse.
Sources: https://doi.org/10.34133/research.0696
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