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BP\u2010MPN represents an unmet need, due to its refractoriness to treatment and dismal outcome. Taking advantage of the granularity provided by single\u2010cell sequencing (SCS), we analyzed paired samples of CP and BP in 10 patients to map clonal trajectories and interrogate target copy number variants (CNVs). Already at diagnosis, MPN present as oligoclonal diseases with varying ratio of mutated and wild\u2010type cells, including cases where normal hematopoiesis was entirely surmised by mutated clones. BP originated from increasing clonal complexity, either on top or independent of a driver mutation, through acquisition of novel mutations as well as accumulation of clones harboring multiple mutations, that were detected at CP by SCS but were missed by bulk sequencing. There were progressive copy\u2010number imbalances from CP to BP, that configured distinct clonal profiles and identified recurrences in genes including<jats:italic>NF1<\/jats:italic>,<jats:italic>TET2<\/jats:italic>, and<jats:italic>BCOR<\/jats:italic>, suggesting an additional level of complexity and contribution to leukemic transformation.<jats:italic>EZH2<\/jats:italic>emerged as the gene most frequently affected by single nucleotide and CNVs, that might result in EZH2\/PRC2\u2010mediated transcriptional deregulation, as supported by combined scATAC\u2010seq and snRNA\u2010seq analysis of the leukemic clone in a representative case. Overall, findings provided insights into the pathogenesis of MPN\u2010BP, identified CNVs as a hitherto poorly characterized mechanism and point to EZH2 dysregulation as target. Serial assessment of clonal dynamics might potentially allow early detection of impending disease transformation, with therapeutic implications.<\/jats:p>","DOI":"10.1002\/ajh.27013","type":"journal-article","created":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T17:45:12Z","timestamp":1688406312000},"page":"1520-1531","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Clonal dynamics and copy number variants by single\u2010cell analysis in leukemic evolution of myeloproliferative neoplasms"],"prefix":"10.1002","volume":"98","author":[{"given":"Laura","family":"Calabresi","sequence":"first","affiliation":[{"name":"Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM) Azienda Ospedaliera\u2010Universitaria Careggi Florence Italy"},{"name":"Department of Experimental and Clinical Medicine University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5952-0818","authenticated-orcid":false,"given":"Chiara","family":"Carretta","sequence":"additional","affiliation":[{"name":"Centre for Regenerative Medicine \"S. 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