Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia
Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia
Abstract The heterogeneity and evolution of AML blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. To gain insight into the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs, we employed whole-exome sequencing and single-cell RNA-seq to longitudinally profile two t(8;21) (AML1-ETO = RUNX1-RUNX1T1), and four FLT3-ITD AML cases. The single cell RNA data underpinned the tumor heterogeneity amongst patient blasts. The Dx-Re transcriptomes of high risk FLT3-ITD pairs formed a continuum from extensively changed in the absence of significantly mutational changes in AML-associated genes to rather similar Dx-Re pair of an intermediate risk FLT3-ITD. In one high risk FLT3-ITD pair, a pathway switched from an AP-1 regulated network in Dx to mTOR signaling in Re. The distinct AML1-ETO pairs comprise clusters that share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells probably evolved from the Dx LSC-like cells. In summary, our study revealed a continuum from drastic transcriptional changes to extensive similarities between respective Dx-Re pairs that are poorly explained by the well-established model of clonal evolution. Our results suggest alternative and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence.
Singh Prashant、Dolnik Anna、Gaudio Nunzio del、D?hner Konstanze、Stunnenberg Hendrik G.、Altucci Lucia、D?hner Hartmut、Atlasy Nader、Martens Joost、Zhai Yanan、Minucci Saverio、Bullinger Lars、Brazda Peter、Megchelenbrink Wout
Prinses Maxima CentrumCharit¨| ¨C Universit?tsmedizin Berlin, corporate member of Freie Universit?t Berlin, Humboldt-Universit?t zu Berlin, and Berlin Institute of Health, Medical Department, Division of Hematology, Oncology, and Cancer Immunology||German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)Department of Precision Medicine, University of Campania ?°Luigi Vanvitelli?±Department of Internal Medicine III, University Hospital of UlmPrinses Maxima Centrum||Department of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life SciencesDepartment of Precision Medicine, University of Campania ?°Luigi Vanvitelli?±||BIOGEM, Institute of Molecular Biology and GeneticsDepartment of Internal Medicine III, University Hospital of UlmDepartment of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life SciencesDepartment of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life SciencesDepartment of Precision Medicine, University of Campania ?°Luigi Vanvitelli?±||Prinses Maxima Centrum||Department of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life SciencesDepartment of Experimental Oncology, European Institute of OncologyCharit¨| ¨C Universit?tsmedizin Berlin, corporate member of Freie Universit?t Berlin, Humboldt-Universit?t zu Berlin, and Berlin Institute of Health, Medical Department, Division of Hematology, Oncology, and Cancer Immunology||German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)Prinses Maxima Centrum||Department of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life SciencesDepartment of Precision Medicine, University of Campania ?°Luigi Vanvitelli?±||Prinses Maxima Centrum
肿瘤学基础医学分子生物学
Singh Prashant,Dolnik Anna,Gaudio Nunzio del,D?hner Konstanze,Stunnenberg Hendrik G.,Altucci Lucia,D?hner Hartmut,Atlasy Nader,Martens Joost,Zhai Yanan,Minucci Saverio,Bullinger Lars,Brazda Peter,Megchelenbrink Wout.Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia[EB/OL].(2025-03-28)[2025-05-22].https://www.biorxiv.org/content/10.1101/2022.01.04.474929.点此复制
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