Mutation order in acute myeloid leukemia identifies uncommon patterns of evolution and illuminates phenotypic heterogeneity Journal Article
| Authors: | Schwede, M.; Jahn, K.; Kuipers, J.; Miles, L. A.; Bowman, R. L.; Robinson, T.; Furudate, K.; Uryu, H.; Tanaka, T.; Sasaki, Y.; Ediriwickrema, A.; Benard, B.; Gentles, A. J.; Levine, R.; Beerenwinkel, N.; Takahashi, K.; Majeti, R. |
| Article Title: | Mutation order in acute myeloid leukemia identifies uncommon patterns of evolution and illuminates phenotypic heterogeneity |
| Abstract: | Acute myeloid leukemia (AML) has a poor prognosis and a heterogeneous mutation landscape. Although common mutations are well-studied, little research has characterized how the sequence of mutations relates to clinical features. Using published, single-cell DNA sequencing data from three institutions, we compared clonal evolution patterns in AML to patient characteristics, disease phenotype, and outcomes. Mutation trees, which represent the order of select mutations, were created for 207 patients from targeted panel sequencing data using 1 639 162 cells, 823 mutations, and 275 samples. In 224 distinct orderings of mutated genes, mutations related to DNA methylation typically preceded those related to cell signaling, but signaling-first cases did occur, and had higher peripheral cell counts, increased signaling mutation homozygosity, and younger patient age. Serial sample analysis suggested that NPM1 and DNA methylation mutations provide an advantage to signaling mutations in AML. Interestingly, WT1 mutation evolution shared features with signaling mutations, such as WT1-early being proliferative and occurring in younger individuals, trends that remained in multivariable regression. Some mutation orderings had a worse prognosis, but this was mediated by unfavorable mutations, not mutation order. These findings add a dimension to the mutation landscape of AML, identifying uncommon patterns of leukemogenesis and shedding light on heterogeneous phenotypes. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | signal transduction; adult; controlled study; human tissue; aged; middle aged; gene mutation; human cell; major clinical study; sequence analysis; genetics; mutation; leukemia, myeloid, acute; clinical feature; nonhuman; phenotype; apoptosis; genetic variability; pathology; dna methylation; homozygosity; bone marrow biopsy; leukemogenesis; cell count; blood cell count; genetic heterogeneity; dna methyltransferase 3a; cd135 antigen; nucleophosmin; single cell analysis; evolutionary adaptation; acute myeloid leukemia; clonal evolution; zygosity; isocitrate dehydrogenase 2; dna sequencing; humans; prognosis; human; male; female; article; phenotypic heterogeneity; enrasentan; npm1 protein, human; blast count; granulocyte count |
| Journal Title: | Leukemia |
| Volume: | 38 |
| Issue: | 7 |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-07-01 |
| Start Page: | 1501 |
| End Page: | 1510 |
| Language: | English |
| DOI: | 10.1038/s41375-024-02211-z |
| PUBMED: | 38467769 |
| PROVIDER: | scopus |
| PMCID: | PMC11250774 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
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