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Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia
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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9389773/ https://www.ncbi.nlm.nih.gov/pubmed/35986270 http://dx.doi.org/10.1186/s12943-022-01635-4 |
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author | Zhai, Yanan Singh, Prashant Dolnik, Anna Brazda, Peter Atlasy, Nader del Gaudio, Nunzio Döhner, Konstanze Döhner, Hartmut Minucci, Saverio Martens, Joost Altucci, Lucia Megchelenbrink, Wout Bullinger, Lars Stunnenberg, Hendrik G. |
author_facet | Zhai, Yanan Singh, Prashant Dolnik, Anna Brazda, Peter Atlasy, Nader del Gaudio, Nunzio Döhner, Konstanze Döhner, Hartmut Minucci, Saverio Martens, Joost Altucci, Lucia Megchelenbrink, Wout Bullinger, Lars Stunnenberg, Hendrik G. |
author_sort | Zhai, Yanan |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-022-01635-4. |
format | Online Article Text |
id | pubmed-9389773 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-93897732022-08-20 Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia Zhai, Yanan Singh, Prashant Dolnik, Anna Brazda, Peter Atlasy, Nader del Gaudio, Nunzio Döhner, Konstanze Döhner, Hartmut Minucci, Saverio Martens, Joost Altucci, Lucia Megchelenbrink, Wout Bullinger, Lars Stunnenberg, Hendrik G. Mol Cancer Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-022-01635-4. BioMed Central 2022-08-19 /pmc/articles/PMC9389773/ /pubmed/35986270 http://dx.doi.org/10.1186/s12943-022-01635-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Zhai, Yanan Singh, Prashant Dolnik, Anna Brazda, Peter Atlasy, Nader del Gaudio, Nunzio Döhner, Konstanze Döhner, Hartmut Minucci, Saverio Martens, Joost Altucci, Lucia Megchelenbrink, Wout Bullinger, Lars Stunnenberg, Hendrik G. Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia |
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 | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9389773/ https://www.ncbi.nlm.nih.gov/pubmed/35986270 http://dx.doi.org/10.1186/s12943-022-01635-4 |
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