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The Molecular Subtype of Adult Acute Lymphoblastic Leukemia Samples Determines the Engraftment Site and Proliferation Kinetics in Patient-Derived Xenograft Models
In acute lymphoblastic leukemia (ALL), conventional cell lines do not recapitulate the clonal diversity and microenvironment. Orthotopic patient-derived xenograft models (PDX) overcome these limitations and mimic the clinical situation, but molecular stability and engraftment patterns have not yet b...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750004/ https://www.ncbi.nlm.nih.gov/pubmed/35011712 http://dx.doi.org/10.3390/cells11010150 |
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author | Richter, Anna Roolf, Catrin Sekora, Anett Knuebel, Gudrun Krohn, Saskia Lange, Sandra Krebs, Vivien Schneider, Bjoern Lakner, Johannes Wittke, Christoph Kiefel, Christoph Jeremias, Irmela Murua Escobar, Hugo Vollmar, Brigitte Junghanss, Christian |
author_facet | Richter, Anna Roolf, Catrin Sekora, Anett Knuebel, Gudrun Krohn, Saskia Lange, Sandra Krebs, Vivien Schneider, Bjoern Lakner, Johannes Wittke, Christoph Kiefel, Christoph Jeremias, Irmela Murua Escobar, Hugo Vollmar, Brigitte Junghanss, Christian |
author_sort | Richter, Anna |
collection | PubMed |
description | In acute lymphoblastic leukemia (ALL), conventional cell lines do not recapitulate the clonal diversity and microenvironment. Orthotopic patient-derived xenograft models (PDX) overcome these limitations and mimic the clinical situation, but molecular stability and engraftment patterns have not yet been thoroughly assessed. We herein describe and characterize the PDX generation in NSG mice. In vivo tumor cell proliferation, engraftment and location were monitored by flow cytometry and bioluminescence imaging. Leukemic cells were retransplanted for up to four passages, and comparative analyses of engraftment pattern, cellular morphology and genomic hotspot mutations were conducted. Ninety-four percent of all samples were successfully engrafted, and the xenograft velocity was dependent on the molecular subtype, outcome of the patient and transplantation passage. While BCR::ABL1 blasts were located in the spleen, KMT2A-positive cases had higher frequencies in the bone marrow. Molecular changes appeared in most model systems, with low allele frequency variants lost during primary engraftment. After the initial xenografting, however, the PDX models demonstrated high molecular stability. This protocol for reliable ALL engraftment demonstrates variability in the location and molecular signatures during serial transplantation. Thorough characterization of experimentally used PDX systems is indispensable for the correct analysis and valid data interpretation of preclinical PDX studies. |
format | Online Article Text |
id | pubmed-8750004 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87500042022-01-12 The Molecular Subtype of Adult Acute Lymphoblastic Leukemia Samples Determines the Engraftment Site and Proliferation Kinetics in Patient-Derived Xenograft Models Richter, Anna Roolf, Catrin Sekora, Anett Knuebel, Gudrun Krohn, Saskia Lange, Sandra Krebs, Vivien Schneider, Bjoern Lakner, Johannes Wittke, Christoph Kiefel, Christoph Jeremias, Irmela Murua Escobar, Hugo Vollmar, Brigitte Junghanss, Christian Cells Article In acute lymphoblastic leukemia (ALL), conventional cell lines do not recapitulate the clonal diversity and microenvironment. Orthotopic patient-derived xenograft models (PDX) overcome these limitations and mimic the clinical situation, but molecular stability and engraftment patterns have not yet been thoroughly assessed. We herein describe and characterize the PDX generation in NSG mice. In vivo tumor cell proliferation, engraftment and location were monitored by flow cytometry and bioluminescence imaging. Leukemic cells were retransplanted for up to four passages, and comparative analyses of engraftment pattern, cellular morphology and genomic hotspot mutations were conducted. Ninety-four percent of all samples were successfully engrafted, and the xenograft velocity was dependent on the molecular subtype, outcome of the patient and transplantation passage. While BCR::ABL1 blasts were located in the spleen, KMT2A-positive cases had higher frequencies in the bone marrow. Molecular changes appeared in most model systems, with low allele frequency variants lost during primary engraftment. After the initial xenografting, however, the PDX models demonstrated high molecular stability. This protocol for reliable ALL engraftment demonstrates variability in the location and molecular signatures during serial transplantation. Thorough characterization of experimentally used PDX systems is indispensable for the correct analysis and valid data interpretation of preclinical PDX studies. MDPI 2022-01-03 /pmc/articles/PMC8750004/ /pubmed/35011712 http://dx.doi.org/10.3390/cells11010150 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Richter, Anna Roolf, Catrin Sekora, Anett Knuebel, Gudrun Krohn, Saskia Lange, Sandra Krebs, Vivien Schneider, Bjoern Lakner, Johannes Wittke, Christoph Kiefel, Christoph Jeremias, Irmela Murua Escobar, Hugo Vollmar, Brigitte Junghanss, Christian The Molecular Subtype of Adult Acute Lymphoblastic Leukemia Samples Determines the Engraftment Site and Proliferation Kinetics in Patient-Derived Xenograft Models |
title | The Molecular Subtype of Adult Acute Lymphoblastic Leukemia Samples Determines the Engraftment Site and Proliferation Kinetics in Patient-Derived Xenograft Models |
title_full | The Molecular Subtype of Adult Acute Lymphoblastic Leukemia Samples Determines the Engraftment Site and Proliferation Kinetics in Patient-Derived Xenograft Models |
title_fullStr | The Molecular Subtype of Adult Acute Lymphoblastic Leukemia Samples Determines the Engraftment Site and Proliferation Kinetics in Patient-Derived Xenograft Models |
title_full_unstemmed | The Molecular Subtype of Adult Acute Lymphoblastic Leukemia Samples Determines the Engraftment Site and Proliferation Kinetics in Patient-Derived Xenograft Models |
title_short | The Molecular Subtype of Adult Acute Lymphoblastic Leukemia Samples Determines the Engraftment Site and Proliferation Kinetics in Patient-Derived Xenograft Models |
title_sort | molecular subtype of adult acute lymphoblastic leukemia samples determines the engraftment site and proliferation kinetics in patient-derived xenograft models |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750004/ https://www.ncbi.nlm.nih.gov/pubmed/35011712 http://dx.doi.org/10.3390/cells11010150 |
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