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Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice

Paczulla, Anna M. and Dirnhofer, Stephan and Konantz, Martina and Medinger, Michael and Salih, Helmut R. and Rothfelder, Kathrin and Tsakiris, Dimitrios A. and Passweg, Jakob R. and Lundberg, Pontus and Lengerke, Claudia. (2017) Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice. Haematologica, 102 (5). pp. 854-864.

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Official URL: https://edoc.unibas.ch/69776/

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Abstract

Repopulation of immunodeficient mice remains the primary method for functional assessment of human acute myeloid leukemia. Published data report engraftment in ~40-66% of cases, mostly of intermediate- or poor-risk subtypes. Here we report that extending follow-up beyond the standard analysis endpoints of 10 to 16 weeks after transplantation permitted leukemic engraftment from nearly every case of xenotransplanted acute myeloid leukemia (18/19, ~95%). Xenogeneic leukemic cells showed conserved immune pheno-types and genetic signatures when compared to corresponding pre-transplant cells and, furthermore, were able to induce leukemia in re-transplantation assays. Importantly, bone marrow biopsies taken at standardized time points failed to detect leukemic cells in 11/18 of cases that later showed robust engraftment (61%, termed "long-latency engrafters"), indicating that leukemic cells can persist over months at undetectable levels without losing disease-initiating properties. Cells from favorable-risk leukemia subtypes required longer to become detectable in NOD/SCID/IL2Rγ; null; mice (27.5±9.4 weeks) than did cells from intermediate-risk (21.9±9.4 weeks,; P; <0.01) or adverse-risk (17±7.6 weeks;; P; <0.0001) subtypes, explaining why the engraftment of the first was missed with previous protocols. Mechanistically, leukemic cells engrafting after a prolonged latency showed inferior homing to the bone marrow. Finally, we applied our model to favorable-risk acute myeloid leukemia with inv(16); here, we showed that CD34; +; (but not CD34; -; ) blasts induced robust, long-latency engraftment and expressed enhanced levels of stem cell genes. In conclusion, we provide a model that allows; in vivo; mouse studies with a wide range of molecular subtypes of acute myeloid leukemia subtypes which were previously considered not able to engraft, thus enabling novel insights into leukemogenesis.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB > Innere Medizin (Bassetti)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB > Innere Medizin (Bassetti)
03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Hämatologie > Hämatologie (Passweg)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Hämatologie > Hämatologie (Passweg)
UniBasel Contributors:Medinger, Michael
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1592-8721
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:09 Apr 2019 15:54
Deposited On:09 Apr 2019 15:54

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