Study reveals a hidden cause of treatment failure in acute promyelocytic leukemia

Study reveals a hidden cause of treatment failure in acute promyelocytic leukemia

Researchers at Zhejiang University School of Medicine have identified a single point mutation in the normalPMLGene that can block the effects of arsenic trioxide, a drug on the front line for acute promyelocytic leukemia. This discovery reveals a hidden cause of treatment failure and suggests a new target for genetic screening in relapsed patients. This work addresses the pressing issue of why some patients relapse despite therapy that otherwise significantly improves survival.

The mutation explains why a small proportion of leukemia patients relapse on arsenic therapy

The arsenic trioxide cures the acute promyelocytic leukemia patients, but some patients reflect without any obvious genetic reason. Discover that mutations occur in the intactPMLAllelic conference resistance provides an opportunity to predict and prevent treatment failure. Clinicians could add this test to standard panels to guide personalized therapy. For diagnostic developers, it indicates the development of new assays. Health care 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 in treatment.

We have long been puzzled as to why a small subset of patients continue to relapse despite the proven effectiveness of arsenic trioxide. This study finally uncovers a hidden genetic factor and brings us closer to preventing these relapses. “

Prof. Hua Naranmandura

A216V alteration of healthy PML locks on fusion protein and reveals a new drug resistance switch

The researchers identified an A216V mutation in the unmetPMLGene of a relapsed patient, while thePML::RARαThe fusion gene did not remain mutated. Cells carrying this mutation failed to affect the disease fusion protein treated with arsenic trioxide, indicating resistance to the treatment. Laboratory models showed that the mutant PML binds more tightly to the PML::RARα protein, preventing drug-induced destabilization of this complex. Importantly, deleting the coiled-coil region of mutant PML abolished this abnormal interaction and restored drug sensitivity, establishing a mechanism for resistance and a possible point of intervention.

Patient sequencing and engineered cells focus on how mutant PML thwarts arsenic-induced breakthroughs

The team sequenced bothPMLAndPML::RARαGenes 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 drug's effects on the leukemia fusion protein. This combination of patient data and controlled cell experiments provided robust, clinically relevant results.

“We hope to add the unrepairedPMLScreening in standard panels is becoming routine,” says Prof. Hua Naranmandura.” Early identification of patients at risk means we can adapt therapy before resistance emerges, ultimately improving survival and reducing costs. “

Published inResearchIn May 2025, this study shows testing the unrepairedPMLAllele is crucial for understanding and overcoming arsenic trioxide resistance in acute promyelocyticemia. Incorporating screening for such mutations into clinical practice could lead to more effective and personalized treatment strategies for relapsed patients.

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