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We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo\u2010AML, 53%), immature myeloid (My\u2010AML, 43%) or erythroid (Ery\u2010AML, 2%). Mo\u2010AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by <jats:italic>SRSF2<\/jats:italic>, <jats:italic>TET2<\/jats:italic> and <jats:italic>RAS<\/jats:italic> pathway mutation co\u2010dominance and were more likely to evolve from <jats:italic>SRSF2\u2010TET2<\/jats:italic> co\u2010mutant CMML through emergence\/expansion of <jats:italic>RAS<\/jats:italic> pathway mutant clones. Conversely, My\u2010AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency\u00a0of CD14, CD64 and CD56 expression) were less likely to exhibit <jats:italic>SRSF2\u2010TET2<\/jats:italic> co\u2010mutations or <jats:italic>RAS<\/jats:italic> pathway mutations and had higher frequency of <jats:italic>CEBPA<\/jats:italic> mutations. Ery\u2010AML was defined by complex karyotypes and <jats:italic>TP53<\/jats:italic> mutations. A\u00a0trend towards improved OS and EFS with hypomethylating agent\u2010venetoclax combination was observed in My\u2010AML, but not Mo\u2010AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype\u2010specific therapeutics.<\/jats:p>","DOI":"10.1111\/bjh.19060","type":"journal-article","created":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T06:02:07Z","timestamp":1692770527000},"page":"581-592","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Phenotypic subtypes of leukaemic transformation in chronic myelomonocytic leukaemia"],"prefix":"10.1111","volume":"203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4533-5176","authenticated-orcid":false,"given":"Guillermo","family":"Montalban\u2010Bravo","sequence":"first","affiliation":[{"name":"Department of Leukemia The University of Texas MD Anderson Cancer Center  Houston Texas 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