Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia
Abstract Background Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts in the hematopoietic system. The heterogeneity and evolution of cance...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-022-01635-4 |
| _version_ | 1811340564730216448 |
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| author | Yanan Zhai Prashant Singh Anna Dolnik Peter Brazda Nader Atlasy Nunzio del Gaudio Konstanze Döhner Hartmut Döhner Saverio Minucci Joost Martens Lucia Altucci Wout Megchelenbrink Lars Bullinger Hendrik G. Stunnenberg |
| author_facet | Yanan Zhai Prashant Singh Anna Dolnik Peter Brazda Nader Atlasy Nunzio del Gaudio Konstanze Döhner Hartmut Döhner Saverio Minucci Joost Martens Lucia Altucci Wout Megchelenbrink Lars Bullinger Hendrik G. Stunnenberg |
| author_sort | Yanan Zhai |
| collection | DOAJ |
| description | Abstract Background Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts in the hematopoietic system. The heterogeneity and evolution of cancer blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. In this study, we investigated the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs at genetic and transcriptional levels, and unveiled the underlying pathways and genes contributing to recurrence. Methods Whole-exome sequencing was used to detect somatic mutations and large copy number variations (CNVs). Single cell RNA-seq was performed to investigate the clonal heterogeneity between Dx-Re pairs and amongst patients. Results scRNA-seq analysis revealed extensive expression differences between patients and Dx-Re pairs, even for those with the same -presumed- initiating events. Transcriptional differences between and within patients are associated with clonal composition and evolution, with the most striking differences in patients that gained large-scale copy number variations at relapse. These differences appear to have significant molecular implications, exemplified by a DNMT3A/FLT3-ITD patient where the leukemia switched from an AP-1 regulated clone at Dx to a mTOR signaling driven clone at Re. The two distinct AML1-ETO pairs share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells evolved from the Dx cells. Conclusions In summary, the single cell RNA data underpinned the tumor heterogeneity not only amongst patient blasts with similar initiating mutations but also between each Dx-Re pair. Our results suggest alternatively and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence. |
| first_indexed | 2024-04-13T18:43:50Z |
| format | Article |
| id | doaj.art-cdc5c6225a8845a29d882f5c207da3a3 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-04-13T18:43:50Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-cdc5c6225a8845a29d882f5c207da3a32022-12-22T02:34:39ZengBMCMolecular Cancer1476-45982022-08-0121111510.1186/s12943-022-01635-4Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemiaYanan Zhai0Prashant Singh1Anna Dolnik2Peter Brazda3Nader Atlasy4Nunzio del Gaudio5Konstanze Döhner6Hartmut Döhner7Saverio Minucci8Joost Martens9Lucia Altucci10Wout Megchelenbrink11Lars Bullinger12Hendrik G. Stunnenberg13Department of Precision Medicine, University of Campania “Luigi Vanvitelli”Prinses Maxima CentrumMedical Department, Division of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of HealthPrinses Maxima CentrumDepartment of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud UniversityDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli”Department of Internal Medicine III, University Hospital of UlmDepartment of Internal Medicine III, University Hospital of UlmDepartment of Experimental Oncology, European Institute of Oncology IRCCSDepartment of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud UniversityDepartment of Precision Medicine, University of Campania “Luigi Vanvitelli”Department of Precision Medicine, University of Campania “Luigi Vanvitelli”Medical Department, Division of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of HealthPrinses Maxima CentrumAbstract Background Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts in the hematopoietic system. The heterogeneity and evolution of cancer blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. In this study, we investigated the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs at genetic and transcriptional levels, and unveiled the underlying pathways and genes contributing to recurrence. Methods Whole-exome sequencing was used to detect somatic mutations and large copy number variations (CNVs). Single cell RNA-seq was performed to investigate the clonal heterogeneity between Dx-Re pairs and amongst patients. Results scRNA-seq analysis revealed extensive expression differences between patients and Dx-Re pairs, even for those with the same -presumed- initiating events. Transcriptional differences between and within patients are associated with clonal composition and evolution, with the most striking differences in patients that gained large-scale copy number variations at relapse. These differences appear to have significant molecular implications, exemplified by a DNMT3A/FLT3-ITD patient where the leukemia switched from an AP-1 regulated clone at Dx to a mTOR signaling driven clone at Re. The two distinct AML1-ETO pairs share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells evolved from the Dx cells. Conclusions In summary, the single cell RNA data underpinned the tumor heterogeneity not only amongst patient blasts with similar initiating mutations but also between each Dx-Re pair. Our results suggest alternatively and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence.https://doi.org/10.1186/s12943-022-01635-4Acute myeloid LeukemiaSingle-cell RNA sequencingRecurrenceLeukemic stem cellsGenome analysis |
| spellingShingle | Yanan Zhai Prashant Singh Anna Dolnik Peter Brazda Nader Atlasy Nunzio del Gaudio Konstanze Döhner Hartmut Döhner Saverio Minucci Joost Martens Lucia Altucci Wout Megchelenbrink Lars Bullinger Hendrik G. Stunnenberg Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia Molecular Cancer Acute myeloid Leukemia Single-cell RNA sequencing Recurrence Leukemic stem cells Genome analysis |
| title | Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia |
| title_full | Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia |
| title_fullStr | Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia |
| title_full_unstemmed | Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia |
| title_short | Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia |
| title_sort | longitudinal single cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia |
| topic | Acute myeloid Leukemia Single-cell RNA sequencing Recurrence Leukemic stem cells Genome analysis |
| url | https://doi.org/10.1186/s12943-022-01635-4 |
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