Cargando…
Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia
To better understand clonal and transcriptional adaptations after relapse in patients with acute myeloid leukemia (AML), we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole-genome sequencing to characterize clonal evolution, and deep-coverag...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924296/ https://www.ncbi.nlm.nih.gov/pubmed/35019859 http://dx.doi.org/10.1158/2643-3230.BCD-21-0050 |
_version_ | 1784887867404713984 |
---|---|
author | Petti, Allegra A. Khan, Saad M. Xu, Ziheng Helton, Nichole Fronick, Catrina C. Fulton, Robert Ramakrishnan, Sai M. Nonavinkere Srivatsan, Sridhar Heath, Sharon E. Westervelt, Peter Payton, Jacqueline E. Walter, Matthew J. Link, Daniel C. DiPersio, John Miller, Christopher Ley, Timothy J. |
author_facet | Petti, Allegra A. Khan, Saad M. Xu, Ziheng Helton, Nichole Fronick, Catrina C. Fulton, Robert Ramakrishnan, Sai M. Nonavinkere Srivatsan, Sridhar Heath, Sharon E. Westervelt, Peter Payton, Jacqueline E. Walter, Matthew J. Link, Daniel C. DiPersio, John Miller, Christopher Ley, Timothy J. |
author_sort | Petti, Allegra A. |
collection | PubMed |
description | To better understand clonal and transcriptional adaptations after relapse in patients with acute myeloid leukemia (AML), we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole-genome sequencing to characterize clonal evolution, and deep-coverage single-cell RNA sequencing on the same samples, which yielded 142,642 high-quality cells for analysis. Identifying expressed mutations in individual cells enabled us to discriminate between normal and AML cells, to identify coordinated changes in the genome and transcriptome, and to identify subclone-specific cell states. We quantified the coevolution of genetic and transcriptional heterogeneity during AML progression, and found that transcriptional changes were significantly correlated with genetic changes. However, transcriptional adaptation sometimes occurred independently, suggesting that clonal evolution does not represent all relevant biological changes. In three cases, we identified cells at diagnosis that likely seeded the relapse. Finally, these data revealed a conserved relapse-enriched leukemic cell state bearing markers of stemness, quiescence, and adhesion. SIGNIFICANCE: These data enabled us to identify a relapse-enriched leukemic cell state with distinct transcriptional properties. Detailed case-by-case analyses elucidated the complex ways in which the AML genome, transcriptome, and immune microenvironment interact to evade chemotherapy. These analyses provide a blueprint for evaluating these factors in larger cohorts. This article is highlighted in the In This Issue feature, p. 1 |
format | Online Article Text |
id | pubmed-9924296 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-99242962023-02-14 Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia Petti, Allegra A. Khan, Saad M. Xu, Ziheng Helton, Nichole Fronick, Catrina C. Fulton, Robert Ramakrishnan, Sai M. Nonavinkere Srivatsan, Sridhar Heath, Sharon E. Westervelt, Peter Payton, Jacqueline E. Walter, Matthew J. Link, Daniel C. DiPersio, John Miller, Christopher Ley, Timothy J. Blood Cancer Discov Research Articles To better understand clonal and transcriptional adaptations after relapse in patients with acute myeloid leukemia (AML), we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole-genome sequencing to characterize clonal evolution, and deep-coverage single-cell RNA sequencing on the same samples, which yielded 142,642 high-quality cells for analysis. Identifying expressed mutations in individual cells enabled us to discriminate between normal and AML cells, to identify coordinated changes in the genome and transcriptome, and to identify subclone-specific cell states. We quantified the coevolution of genetic and transcriptional heterogeneity during AML progression, and found that transcriptional changes were significantly correlated with genetic changes. However, transcriptional adaptation sometimes occurred independently, suggesting that clonal evolution does not represent all relevant biological changes. In three cases, we identified cells at diagnosis that likely seeded the relapse. Finally, these data revealed a conserved relapse-enriched leukemic cell state bearing markers of stemness, quiescence, and adhesion. SIGNIFICANCE: These data enabled us to identify a relapse-enriched leukemic cell state with distinct transcriptional properties. Detailed case-by-case analyses elucidated the complex ways in which the AML genome, transcriptome, and immune microenvironment interact to evade chemotherapy. These analyses provide a blueprint for evaluating these factors in larger cohorts. This article is highlighted in the In This Issue feature, p. 1 American Association for Cancer Research 2022-01 2021-08-24 /pmc/articles/PMC9924296/ /pubmed/35019859 http://dx.doi.org/10.1158/2643-3230.BCD-21-0050 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Research Articles Petti, Allegra A. Khan, Saad M. Xu, Ziheng Helton, Nichole Fronick, Catrina C. Fulton, Robert Ramakrishnan, Sai M. Nonavinkere Srivatsan, Sridhar Heath, Sharon E. Westervelt, Peter Payton, Jacqueline E. Walter, Matthew J. Link, Daniel C. DiPersio, John Miller, Christopher Ley, Timothy J. Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia |
title | Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia |
title_full | Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia |
title_fullStr | Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia |
title_full_unstemmed | Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia |
title_short | Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia |
title_sort | genetic and transcriptional contributions to relapse in normal karyotype acute myeloid leukemia |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924296/ https://www.ncbi.nlm.nih.gov/pubmed/35019859 http://dx.doi.org/10.1158/2643-3230.BCD-21-0050 |
work_keys_str_mv | AT pettiallegraa geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT khansaadm geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT xuziheng geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT heltonnichole geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT fronickcatrinac geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT fultonrobert geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT ramakrishnansaim geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT nonavinkeresrivatsansridhar geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT heathsharone geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT westerveltpeter geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT paytonjacquelinee geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT waltermatthewj geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT linkdanielc geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT dipersiojohn geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT millerchristopher geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia AT leytimothyj geneticandtranscriptionalcontributionstorelapseinnormalkaryotypeacutemyeloidleukemia |