{"doi":"10.1101/2023.12.08.570880","title":"Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of <i>DYRK1A</i>","abstract":"Summary 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":393918,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1168709,"name":"BH Yip","orcid":null,"position":1,"is_corresponding":false},{"id":1168416,"name":"Giulia Orlando","orcid":"0000-0002-8917-0246","position":2,"is_corresponding":false},{"id":802156,"name":"Hemant Goyal","orcid":"0000-0002-9433-9042","position":3,"is_corresponding":false},{"id":640591,"name":"Simeng Wen","orcid":"0000-0001-7989-7700","position":4,"is_corresponding":false},{"id":1168417,"name":"Jing Wen","orcid":"0000-0002-5212-1053","position":5,"is_corresponding":false},{"id":1168710,"name":"MF Levine","orcid":null,"position":6,"is_corresponding":false},{"id":1168418,"name":"G. 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