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The median interval between CMML and sAML samples collection was 14.9\u2009months (1.0\u201389.6). <jats:italic>RUNX1<\/jats:italic> (57%), <jats:italic>TET2<\/jats:italic> (46%), <jats:italic>SRSF2<\/jats:italic> (37%), and <jats:italic>ASXL1<\/jats:italic> (28%) mutations were frequent at CMML diagnosis. Baseline VAF in epigenetic regulator genes was high (&gt;35%) in 83% of mutational events at the CMML phase, remained stable in 78% (VAF changes &lt;10%), and increased in 20% (increased VAF\u2009&gt;\u200910%) during progression to sAML. Transcription factor genes showed high VAF (&gt;35%) in 51% at the CMML phase, and stable VAF in 60% during progression. VAF of spliceosome genes was high (&gt;35%) in 70% at CMML phase, and stable in 61% during progression. Activated signaling genes exhibited acquisition or loss during progression. <jats:italic>TET2<\/jats:italic> mutations were often founding clones, and <jats:italic>SRSF2<\/jats:italic>, <jats:italic>ASXL1<\/jats:italic>, <jats:italic>DNMT3A<\/jats:italic>, <jats:italic>EZH2<\/jats:italic>, or spliceosome genes also acted as ancestral mutations. <jats:italic>RUNX1<\/jats:italic> mutations were typically later events and occasionally ancestral hits or germline mutations. Acquisition of cytogenetic changes, signaling pathways genes (<jats:italic>PTPN11<\/jats:italic>, <jats:italic>FLT3<\/jats:italic>, <jats:italic>NRAS<\/jats:italic>, <jats:italic>CBL<\/jats:italic>), or AML\u2010defined genes (<jats:italic>NPM1<\/jats:italic>, <jats:italic>CEBPA<\/jats:italic>, <jats:italic>CBFB<\/jats:italic>::<jats:italic>MYH11<\/jats:italic>) by linear or branching evolution occurred during sAML progression. CN\u2010LOH was noted in <jats:italic>EZH2<\/jats:italic>, <jats:italic>CBL<\/jats:italic>, <jats:italic>TET2<\/jats:italic>, and <jats:italic>DNMT3A<\/jats:italic> genes. <jats:italic>CEBPA<\/jats:italic> mutation and concurrent biallelic <jats:italic>TET2<\/jats:italic> with <jats:italic>NRAS<\/jats:italic> mutations at CMML diagnosis were risk factors for time to AML progression and overall survival. A characteristic <jats:italic>ASXL1<\/jats:italic><jats:sup>MT<\/jats:sup>\/<jats:italic>RUNX1<\/jats:italic><jats:sup>MT<\/jats:sup>\/Spliceosome<jats:sup>MT<\/jats:sup>\/signaling<jats:sup>WT<\/jats:sup> genetic profile was associated with monocyte counts of 0.5\u20131.0\u2009\u00d7\u200910<jats:sup>9<\/jats:sup>\/l. This study highlights the complexity and heterogeneity of dynamic changes in clonal architecture during CMML progression, emphasizing its importance in pathogenesis, phenotype, risk stratification, and therapeutic strategy. \u00a9 2025 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6396","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T03:14:41Z","timestamp":1738725281000},"page":"437-447","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clonal dynamics of chronic myelomonocytic leukemia progression: paired\u2010sample comparison"],"prefix":"10.1002","volume":"265","author":[{"given":"Hsiao\u2010Wen","family":"Kao","sequence":"first","affiliation":[{"name":"Division of Hematology\u2010Oncology, Department of Internal Medicine Chang Gung Memorial Hospital at Linkou  Taoyuan 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