A research team at the University of Oxford has identified a potential new therapeutic target for blast phase myeloproliferative neoplasm (BP-MPN), an aggressive form of leukaemia. The study, published in Nature Genetics, examined the role of chromothripsis—a process where chromosomes break and reassemble chaotically—in BP-MPN, which is known for its resistance to treatment.
Led by the Mead Group at the MRC Weatherall Institute of Molecular Medicine, researchers discovered that 25% of BP-MPN patients had an abnormal gain of genetic material from chromosome 21, termed chr21amp. The study analyzed samples from 64 BP-MPN patients and found that chromothripsis contributed to this genetic anomaly, impacting cancer genomes significantly.
The research, supported by the National Institute for Health and Care Research Oxford Biomedical Research Centre, indicated that chromosome amplification was associated with poorer patient outcomes in BP-MPN. Within this amplified region, the gene DYRK1A was consistently overexpressed and more accessible in cancer cells with this abnormality.
Experiments demonstrated that BP-MPN leukaemia cells rely heavily on DYRK1A for survival and growth. Inhibiting DYRK1A through genetic knockdown or chemical inhibitors notably weakened the cancer cells in laboratory and animal models.
Lead author Charlotte Brierley stated: "Together, these findings suggest that chr21amp is not only a marker of poor prognosis in BP-MPN but also points to DYRK1A as a promising druggable target that arises specifically from chromothripsis-related changes in the cancer genome."
Professor Adam Mead, who supervised the study, commented: "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. As a next step we are exploring the possibility of starting a clinical trial using already available DYRK1A inhibitors."
The full paper titled 'Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A' is available in Nature Genetics.