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Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion

BACKGROUND: Clonal competition in cancer describes the process in which the progeny of a cell clone supersedes or succumbs to other competing clones due to differences in their functional characteristics, mostly based on subsequently acquired mutations. Even though the patterns of those mutations ar...

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Autores principales: Cornils, Kerstin, Thielecke, Lars, Winkelmann, Doreen, Aranyossy, Tim, Lesche, Mathias, Dahl, Andreas, Roeder, Ingo, Fehse, Boris, Glauche, Ingmar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512731/
https://www.ncbi.nlm.nih.gov/pubmed/28709463
http://dx.doi.org/10.1186/s12943-017-0668-x
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author Cornils, Kerstin
Thielecke, Lars
Winkelmann, Doreen
Aranyossy, Tim
Lesche, Mathias
Dahl, Andreas
Roeder, Ingo
Fehse, Boris
Glauche, Ingmar
author_facet Cornils, Kerstin
Thielecke, Lars
Winkelmann, Doreen
Aranyossy, Tim
Lesche, Mathias
Dahl, Andreas
Roeder, Ingo
Fehse, Boris
Glauche, Ingmar
author_sort Cornils, Kerstin
collection PubMed
description BACKGROUND: Clonal competition in cancer describes the process in which the progeny of a cell clone supersedes or succumbs to other competing clones due to differences in their functional characteristics, mostly based on subsequently acquired mutations. Even though the patterns of those mutations are well explored in many tumors, the dynamical process of clonal selection is underexposed. METHODS: We studied the dynamics of clonal competition in a BcrAbl-induced leukemia using a γ-retroviral vector library encoding the oncogene in conjunction with genetic barcodes. To this end, we studied the growth dynamics of transduced cells on the clonal level both in vitro and in vivo in transplanted mice. RESULTS: While we detected moderate changes in clonal abundancies in vitro, we observed monoclonal leukemias in 6/30 mice after transplantation, which intriguingly were caused by only two different BcrAbl clones. To analyze the success of these clones, we applied a mathematical model of hematopoietic tissue maintenance, which indicated that a differential engraftment capacity of these two dominant clones provides a possible explanation of our observations. These findings were further supported by additional transplantation experiments and increased BcrAbl transcript levels in both clones. CONCLUSION: Our findings show that clonal competition is not an absolute process based on mutations, but highly dependent on selection mechanisms in a given environmental context. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-017-0668-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-55127312017-07-19 Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion Cornils, Kerstin Thielecke, Lars Winkelmann, Doreen Aranyossy, Tim Lesche, Mathias Dahl, Andreas Roeder, Ingo Fehse, Boris Glauche, Ingmar Mol Cancer Research BACKGROUND: Clonal competition in cancer describes the process in which the progeny of a cell clone supersedes or succumbs to other competing clones due to differences in their functional characteristics, mostly based on subsequently acquired mutations. Even though the patterns of those mutations are well explored in many tumors, the dynamical process of clonal selection is underexposed. METHODS: We studied the dynamics of clonal competition in a BcrAbl-induced leukemia using a γ-retroviral vector library encoding the oncogene in conjunction with genetic barcodes. To this end, we studied the growth dynamics of transduced cells on the clonal level both in vitro and in vivo in transplanted mice. RESULTS: While we detected moderate changes in clonal abundancies in vitro, we observed monoclonal leukemias in 6/30 mice after transplantation, which intriguingly were caused by only two different BcrAbl clones. To analyze the success of these clones, we applied a mathematical model of hematopoietic tissue maintenance, which indicated that a differential engraftment capacity of these two dominant clones provides a possible explanation of our observations. These findings were further supported by additional transplantation experiments and increased BcrAbl transcript levels in both clones. CONCLUSION: Our findings show that clonal competition is not an absolute process based on mutations, but highly dependent on selection mechanisms in a given environmental context. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-017-0668-x) contains supplementary material, which is available to authorized users. BioMed Central 2017-07-14 /pmc/articles/PMC5512731/ /pubmed/28709463 http://dx.doi.org/10.1186/s12943-017-0668-x Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Cornils, Kerstin
Thielecke, Lars
Winkelmann, Doreen
Aranyossy, Tim
Lesche, Mathias
Dahl, Andreas
Roeder, Ingo
Fehse, Boris
Glauche, Ingmar
Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
title Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
title_full Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
title_fullStr Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
title_full_unstemmed Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
title_short Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
title_sort clonal competition in bcrabl-driven leukemia: how transplantations can accelerate clonal conversion
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512731/
https://www.ncbi.nlm.nih.gov/pubmed/28709463
http://dx.doi.org/10.1186/s12943-017-0668-x
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