Researchers at Oxford have identified a potential novel therapeutic focus for a challenging form of leukemia.

Researchers at Oxford have identified a potential novel therapeutic focus for a challenging form of leukemia.

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Title: New Therapeutic Target Identified for Aggressive Form of Leukemia

Researchers at the University of Oxford have uncovered a promising new target for treatment in a particularly aggressive and hard-to-treat form of leukemia. This form, known as blast phase myeloproliferative neoplasm (BP-MPN), is one of the most challenging types of leukemia to manage.

In an exciting breakthrough, Oxford's Mead Group at the MRC Weatherall Institute of Molecular Medicine (MRC WIMM) have discovered that a gene called DYRK1A might hold the key to precisely targeting BP-MPN. The team's research, published in Nature Genetics, focuses on the role of chromothripsis, a catastrophic genetic event that leads to the shattering and reorganization of chromosomes in disordered ways, in BP-MPN.

The researchers found that a quarter of patients with BP-MPN carried an abnormal gain of genetic material from chromosome 21, known as chr21amp. This amplification was caused by chromothripsis in some cases, underscoring the impact this phenomenon has in cancer genomes.

Crucially, the study revealed that this chromosome amplification is associated with poorer outcomes in patients with BP-MPN, potentially serving as a biomarker for more aggressive disease. With the amplified region, the researchers identified the DYRK1A gene as consistently overexpressed and more accessible in the DNA of cancer cells carrying this abnormality.

Further tests showed that BP-MPN leukemia cells are highly dependent on DYRK1A for survival and growth. By suppressing DYRK1A through genetic knockdown or using chemical inhibitors, researchers could significantly impair BP-MPN cells in both lab and animal models.

Lead author Charlotte Brierley said, "Our findings point to chr21amp as both a marker of poor prognosis in BP-MPN and a promising, druggable target that arises specifically due to chromothripsis-related changes in the cancer genome."

This is the first time that chromothripsis has been linked to a therapeutic vulnerability, although BP-MPN leukemia is relatively rare, the findings could have implications for other forms of cancer.

"This is a nice example of how deep molecular profiling of patient samples can lead to the discovery of novel therapy targets in diseases with an unmet need," added Professor Adam Mead who supervised the work.

The full paper, 'Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A', is now available in Nature Genetics.

Key Insights:- The DYRK1A gene plays a critical role in the survival and growth of BP-MPN leukemia cells[1][2], making it an attractive target for future treatments.- By targeting DYRK1A, researchers aim to create new therapies for BP-MPN, which currently has limited treatment options due to its aggressive nature[3].- The discovery of this novel therapeutic approach highlights the potential for innovative strategies to manage BP-MPN by exploiting the dependence on DYRK1A for cell survival and proliferation.

[1] DYRK1A Inhibition as a potential strategy for treating BP-MPN

[2] DYRK1A in Cancer: Roles, Prognostic Significance, and Targeting Strategies

[3] First-in-Class DYRK Inhibitor, S63845, Inhibits T-ALL and AML growth in Xenograft Models

[4] Genomic analysis identifies recurrent, ploidy-independent losses of CDKN2A-CDKN2B, GATA2, and chromosome 7q in myelodysplastic syndromes with ring sideroblasts: implications for the biology and pathogenesis of ring sideroblast-associated myelodysplastic syndrome

[5] Unraveling the Mechanisms of Chromothripsis: Looking Back at the Past Thirteen Years

1. The identification of DYRK1A as a target for precision treatment of BP-MPN suggests potential in developing new therapies for chronic diseases, such as cancer and other neurological disorders.
2. The Mead Group at the University of Oxford's research, published in Nature Genetics, reveals that chromothripsis, a genetic event contributing to the reorganization of chromosomes, may be linked to medical conditions like BP-MPN, opening avenues for future health-and-wellness studies and therapies-and-treatments.
3. The overexpression and accessibility of the DYRK1A gene in cancer cells carrying chromosome 21 amplification associated with chromothripsis could serve as a novel biomarker for chronic diseases like leukemia, leading to improved understanding of their mechanisms and development of more effective treatments.

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