Researchers uncover a potential new therapeutic target for a hard-to-treat form of leukemia microbiologystudy

A new target for potential treatments for blast phase myeloproliferative neoplasm (BP-MPN), one of the most aggressive forms of leukemia, has been identified by a research team at the University of Oxford.

The paper, “Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A,” was published in Nature Genetics.

In the study, researchers investigated the role of chromothripsis—a dramatic event in which chromosomes shatter and are stitched back together in disordered ways—in BP-MPN, a characteristically treatment-resistant type of leukemia.

The team, led by the Mead Group at the MRC Weatherall Institute of Molecular Medicine (MRC WIMM), found that a quarter of patients with BP-MPN carried an abnormal gain of genetic material from chromosome 21, known as chr21amp.

The team analyzed samples from 64 patients with BP-MPN. In some cases, this abnormal gain was caused by chromothripsis, highlighting the disruptive impact of this phenomenon in cancer genomes.

Crucially, the study showed that this chromosome amplification was linked to poorer outcomes in patients with BP-MPN, making it a potential biomarker for more aggressive disease.

Within the amplified region, researchers identified a single gene, DYRK1A, as consistently overexpressed and more accessible in the DNA of cancer cells carrying this abnormality.

Further experiments revealed that the BP-MPN leukemia cells are highly dependent on DYRK1A for survival and growth. Blocking DYRK1A—either by genetic knockdown or using chemical inhibitors—significantly impaired the cancer cells in both lab and animal models.

Lead author Charlotte Brierley said, “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.

This is the first time that chromothripsis has been linked to a therapeutic vulnerability. Although BP-MPN leukemia is rare, these findings could be applicable in other forms of cancer.”

Professor Adam Mead, who supervised the work, said, “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.”