Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A.
Brierley CK., Yip BH., Orlando G., Goyal H., Wen S., Wen J., Levine MF., Jakobsdottir GM., Rodriguez-Meira A., Adamo A., Bashton M., Hamblin A., Clark SA., O'Sullivan J., Murphy L., Olijnik AA., Cotton A., Narina S., Pruett-Miller SM., Enshaei A., Harrison C., Drummond M., Knapper S., Tefferi A., Antony-Debré I., Thongjuea S., Wedge DC., Constantinescu S., Papaemmanuil E., Psaila B., Crispino JD., Mead AJ.
Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.