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Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin ac...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362028/ https://www.ncbi.nlm.nih.gov/pubmed/37479893 http://dx.doi.org/10.1038/s42003-023-05120-6 |
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author | Fan, Huihui Wang, Feng Zeng, Andy Murison, Alex Tomczak, Katarzyna Hao, Dapeng Jelloul, Fatima Zahra Wang, Bofei Barrodia, Praveen Liang, Shaoheng Chen, Ken Wang, Linghua Zhao, Zhongming Rai, Kunal Jain, Abhinav K. Dick, John Daver, Naval Futreal, Andy Abbas, Hussein A. |
author_facet | Fan, Huihui Wang, Feng Zeng, Andy Murison, Alex Tomczak, Katarzyna Hao, Dapeng Jelloul, Fatima Zahra Wang, Bofei Barrodia, Praveen Liang, Shaoheng Chen, Ken Wang, Linghua Zhao, Zhongming Rai, Kunal Jain, Abhinav K. Dick, John Daver, Naval Futreal, Andy Abbas, Hussein A. |
author_sort | Fan, Huihui |
collection | PubMed |
description | Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, therapy-resistant AML cells are also composed of cells primed for differentiated myeloid, erythroid and even lymphoid lineages. The heterogeneous lineage composition persists following subsequent therapy, with early progenitor-driven features marking unfavorable prognosis in The Cancer Genome Atlas AML cohort. Pseudotime analysis further confirms the vast degree of heterogeneity driven by the dynamic changes in chromatin accessibility. Our findings suggest that therapy-resistant AML cells are characterized not only by stem and progenitor states, but also by a continuum of differentiated cellular lineages. The heterogeneity in lineages likely contributes to their therapy resistance by harboring different degrees of lineage-specific susceptibilities to therapy. |
format | Online Article Text |
id | pubmed-10362028 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-103620282023-07-23 Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance Fan, Huihui Wang, Feng Zeng, Andy Murison, Alex Tomczak, Katarzyna Hao, Dapeng Jelloul, Fatima Zahra Wang, Bofei Barrodia, Praveen Liang, Shaoheng Chen, Ken Wang, Linghua Zhao, Zhongming Rai, Kunal Jain, Abhinav K. Dick, John Daver, Naval Futreal, Andy Abbas, Hussein A. Commun Biol Article Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, therapy-resistant AML cells are also composed of cells primed for differentiated myeloid, erythroid and even lymphoid lineages. The heterogeneous lineage composition persists following subsequent therapy, with early progenitor-driven features marking unfavorable prognosis in The Cancer Genome Atlas AML cohort. Pseudotime analysis further confirms the vast degree of heterogeneity driven by the dynamic changes in chromatin accessibility. Our findings suggest that therapy-resistant AML cells are characterized not only by stem and progenitor states, but also by a continuum of differentiated cellular lineages. The heterogeneity in lineages likely contributes to their therapy resistance by harboring different degrees of lineage-specific susceptibilities to therapy. Nature Publishing Group UK 2023-07-21 /pmc/articles/PMC10362028/ /pubmed/37479893 http://dx.doi.org/10.1038/s42003-023-05120-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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/) . |
spellingShingle | Article Fan, Huihui Wang, Feng Zeng, Andy Murison, Alex Tomczak, Katarzyna Hao, Dapeng Jelloul, Fatima Zahra Wang, Bofei Barrodia, Praveen Liang, Shaoheng Chen, Ken Wang, Linghua Zhao, Zhongming Rai, Kunal Jain, Abhinav K. Dick, John Daver, Naval Futreal, Andy Abbas, Hussein A. Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance |
title | Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance |
title_full | Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance |
title_fullStr | Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance |
title_full_unstemmed | Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance |
title_short | Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance |
title_sort | single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362028/ https://www.ncbi.nlm.nih.gov/pubmed/37479893 http://dx.doi.org/10.1038/s42003-023-05120-6 |
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