Chromothripsis is a massive genomic rearrangement event caused by the shattering and haphazard reassembly of chromosomal segments. A key mechanism for oncogene amplification and the loss of tumor suppressor genes, chromothripsis is pervasive in cancer and associated with poor prognosis. It contributes to 7% of acute myeloid leukemias (AMLs) unrelated to prior diagnoses of myeloproliferative neoplasms (MPNs), slow-growing blood cancers that can develop into AML. But its role in driving MPNs was not well understood. Charlotte Brierley, a clinician-scientist in the groups of Ludwig Oxford’s Bethan Psaila and Adam Mead at the University of Oxford—all of whom led this study and participate in the collaborative MPN Program launched this year at the Oxford Branch—explored the phenomenon in a cohort of 64 patients with blast phase MPN (BP-MPN), an aggressive manifestation of the cancer. They reported in Nature Genetics in June a recurrent amplification of a region of chromosome 21q (chr. 21amp) in a quarter of the cohort. A third of these cases were driven by chromothripsis and had a particularly aggressive and treatment-resistant phenotype. The findings define chr. 21amp as a prognostic biomarker in BP-MPN. The researchers also identified DYRK1A as a potential therapeutic target. A serine-threonine kinase central to BP-MPN development, DYRK1A was the only gene that showed both increased expression and chromatin accessibility in the amplified region of chromothripsis-driven MPNs.
Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
Nature Genetics, 2025 June 9