New Therapeutic Target Identified for Aggressive Leukemia Using Chromothripsis Analysis

Researchers at the University of Oxford have made a significant breakthrough in understanding and potentially treating blast phase myeloproliferative neoplasm (BP-MPN), a highly aggressive and treatment-resistant form of leukemia. Their study, published in Nature Genetics, uncovers a novel therapeutic target linked to genetic alterations caused by chromothripsis—a catastrophic chromosomal shattering and reassembly process.

In their investigation, the team examined samples from 64 BP-MPN patients and discovered that approximately 25% exhibited an abnormal gain of genetic material from chromosome 21, termed chr21amp. This abnormality was often attributable to chromothripsis, emphasizing its role in disrupting cancer genomes. Notably, the presence of chr21amp was associated with poorer clinical outcomes, suggesting its potential as a biomarker for disease severity.

Further genetic analysis identified the gene DYRK1A within the amplified region as being consistently overexpressed in affected cancer cells. The leukemia cells that harbored this amplification showed a high dependency on DYRK1A for survival and proliferation. Laboratory experiments demonstrated that inhibiting DYRK1A—either genetically or chemically—could markedly impair leukemia cell growth in vitro and in animal models.

The study's lead author, Charlotte Brierley, explained that these findings position chr21amp not only as a marker of prognosis but also as a gateway to targeted therapies. The research provides the first evidence linking chromothripsis to a specific therapeutic vulnerability, opening pathways for new treatments. Although BP-MPN is rare, the implications of this discovery could extend to other cancers involving chromothripsis.

Professor Adam Mead highlighted that deep molecular profiling of patient samples is crucial for identifying novel therapeutic targets in difficult-to-treat diseases. The researchers are now exploring clinical trials utilizing existing DYRK1A inhibitors, aiming to translate their findings into effective treatments.

This groundbreaking research underscores the potential of genomic analysis to revolutionize cancer therapy by revealing specific genetic dependencies that can be targeted for better patient outcomes.

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