Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A

Brierley, C. K.; Yip, B. H.; Orlando, G.; Goyal, H.; Wen, S.; Wen, J.; Levine, M. F.; Jakobsdottir, M. G.; Rodriguez-Meira, A.; Adamo, A.; Bashton, M.; Hamblin, A.; Clark, S. A.; O'Sullivan, J.; Murphi, L.; Olijnik-French, A.-A.; Cotton, A.; Narina, S.; Pruett-Miller, S.; Enshaei, A.; Harrison, C.; Drummond, M.; Knapper, S.; Tefferi, A.; Antony-Debre, I.; Thongjuea, S.; Wedge, D. C.; Constantinescu, S.; Papaemmanuil, E.; Psaila, B.; Crispino, J. D.; Mead, A. J.

doi:10.1101/2023.12.08.570880

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bioRxiv · 10.1101/2023.12.08.570880

Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A

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Abstract

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.

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Brierley, C. K., Yip, B. H., Orlando, G., Goyal, H., Wen, S., Wen, J., Levine, M. F., Jakobsdottir, M. G., Rodriguez-Meira, A., Adamo, A., Bashton, M., Hamblin, A., Clark, S. A., O'Sullivan, J., Murphi, L., Olijnik-French, A.-A., Cotton, A., Narina, S., Pruett-Miller, S., Enshaei, A., Harrison, C., Drummond, M., Knapper, S., Tefferi, A., Antony-Debre, I., Thongjuea, S., Wedge, D. C., Constantinescu, S., Papaemmanuil, E., Psaila, B., Crispino, J. D., Mead, A. J.. 2023-12-10. Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A. https://doi.org/10.1101/2023.12.08.570880

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