Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784631362523758592
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
work_keys_str_mv AT richteranna themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT roolfcatrin themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT sekoraanett themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT knuebelgudrun themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT krohnsaskia themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT langesandra themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT krebsvivien themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT schneiderbjoern themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT laknerjohannes themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT wittkechristoph themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT kiefelchristoph themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT jeremiasirmela themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT muruaescobarhugo themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT vollmarbrigitte themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT junghansschristian themolecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT richteranna molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT roolfcatrin molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT sekoraanett molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT knuebelgudrun molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT krohnsaskia molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT langesandra molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT krebsvivien molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT schneiderbjoern molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT laknerjohannes molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT wittkechristoph molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT kiefelchristoph molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT jeremiasirmela molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT muruaescobarhugo molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT vollmarbrigitte molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels
AT junghansschristian molecularsubtypeofadultacutelymphoblasticleukemiasamplesdeterminestheengraftmentsiteandproliferationkineticsinpatientderivedxenograftmodels