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...

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Bibliographic Details
Main Authors: Anna Richter, Catrin Roolf, Anett Sekora, Gudrun Knuebel, Saskia Krohn, Sandra Lange, Vivien Krebs, Bjoern Schneider, Johannes Lakner, Christoph Wittke, Christoph Kiefel, Irmela Jeremias, Hugo Murua Escobar, Brigitte Vollmar, Christian Junghanss
Format: Article
Language:English
Published: MDPI AG 2022-01-01
Series:Cells
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Online Access:https://www.mdpi.com/2073-4409/11/1/150
Description
Summary: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 <i>BCR::ABL1</i> blasts were located in the spleen, <i>KMT2A</i>-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.
ISSN:2073-4409