Hsiao-Wen Kao, Ming-Chung Kuo, Che-Wei Ou, Ting-Yu Huang, Hung Chang, Tung-Liang Lin, Yu-Shin Hung, Jin-Hou Wu, Lee-Yung Shih
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{"title":"Clonal dynamics of chronic myelomonocytic leukemia progression: paired-sample comparison","authors":"Hsiao-Wen Kao, Ming-Chung Kuo, Che-Wei Ou, Ting-Yu Huang, Hung Chang, Tung-Liang Lin, Yu-Shin Hung, Jin-Hou Wu, Lee-Yung Shih","doi":"10.1002/path.6396","DOIUrl":null,"url":null,"abstract":"<p>This study investigated the clonal evolution of chronic myelomonocytic leukemia (CMML) progression to secondary acute myeloid leukemia (sAML) by next-generation sequencing and pyrosequencing for variant allele frequency (VAF) of gene mutations and SNP microarray for copy neutral loss of heterozygosity (CN-LOH) in 38 paired samples from CMML/sAML patients of Taiwanese origin. The median interval between CMML and sAML samples collection was 14.9 months (1.0–89.6). <i>RUNX1</i> (57%), <i>TET2</i> (46%), <i>SRSF2</i> (37%), and <i>ASXL1</i> (28%) mutations were frequent at CMML diagnosis. Baseline VAF in epigenetic regulator genes was high (>35%) in 83% of mutational events at the CMML phase, remained stable in 78% (VAF changes <10%), and increased in 20% (increased VAF > 10%) during progression to sAML. Transcription factor genes showed high VAF (>35%) in 51% at the CMML phase, and stable VAF in 60% during progression. VAF of spliceosome genes was high (>35%) in 70% at CMML phase, and stable in 61% during progression. Activated signaling genes exhibited acquisition or loss during progression. <i>TET2</i> mutations were often founding clones, and <i>SRSF2</i>, <i>ASXL1</i>, <i>DNMT3A</i>, <i>EZH2</i>, or spliceosome genes also acted as ancestral mutations. <i>RUNX1</i> mutations were typically later events and occasionally ancestral hits or germline mutations. Acquisition of cytogenetic changes, signaling pathways genes (<i>PTPN11</i>, <i>FLT3</i>, <i>NRAS</i>, <i>CBL</i>), or AML-defined genes (<i>NPM1</i>, <i>CEBPA</i>, <i>CBFB</i>::<i>MYH11</i>) by linear or branching evolution occurred during sAML progression. CN-LOH was noted in <i>EZH2</i>, <i>CBL</i>, <i>TET2</i>, and <i>DNMT3A</i> genes. <i>CEBPA</i> mutation and concurrent biallelic <i>TET2</i> with <i>NRAS</i> mutations at CMML diagnosis were risk factors for time to AML progression and overall survival. A characteristic <i>ASXL1</i><sup>MT</sup>/<i>RUNX1</i><sup>MT</sup>/Spliceosome<sup>MT</sup>/signaling<sup>WT</sup> genetic profile was associated with monocyte counts of 0.5–1.0 × 10<sup>9</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. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 4","pages":"437-447"},"PeriodicalIF":5.6000,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/path.6396","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
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Abstract
This study investigated the clonal evolution of chronic myelomonocytic leukemia (CMML) progression to secondary acute myeloid leukemia (sAML) by next-generation sequencing and pyrosequencing for variant allele frequency (VAF) of gene mutations and SNP microarray for copy neutral loss of heterozygosity (CN-LOH) in 38 paired samples from CMML/sAML patients of Taiwanese origin. The median interval between CMML and sAML samples collection was 14.9 months (1.0–89.6). RUNX1 (57%), TET2 (46%), SRSF2 (37%), and ASXL1 (28%) mutations were frequent at CMML diagnosis. Baseline VAF in epigenetic regulator genes was high (>35%) in 83% of mutational events at the CMML phase, remained stable in 78% (VAF changes <10%), and increased in 20% (increased VAF > 10%) during progression to sAML. Transcription factor genes showed high VAF (>35%) in 51% at the CMML phase, and stable VAF in 60% during progression. VAF of spliceosome genes was high (>35%) in 70% at CMML phase, and stable in 61% during progression. Activated signaling genes exhibited acquisition or loss during progression. TET2 mutations were often founding clones, and SRSF2 , ASXL1 , DNMT3A , EZH2 , or spliceosome genes also acted as ancestral mutations. RUNX1 mutations were typically later events and occasionally ancestral hits or germline mutations. Acquisition of cytogenetic changes, signaling pathways genes (PTPN11 , FLT3 , NRAS , CBL ), or AML-defined genes (NPM1 , CEBPA , CBFB ::MYH11 ) by linear or branching evolution occurred during sAML progression. CN-LOH was noted in EZH2 , CBL , TET2 , and DNMT3A genes. CEBPA mutation and concurrent biallelic TET2 with NRAS mutations at CMML diagnosis were risk factors for time to AML progression and overall survival. A characteristic ASXL1 MT /RUNX1 MT /SpliceosomeMT /signalingWT genetic profile was associated with monocyte counts of 0.5–1.0 × 109 /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. © 2025 The Pathological Society of Great Britain and Ireland.