Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice
Anna M. Paczulla,
Stephan Dirnhofer,
Martina Konantz,
Michael Medinger,
Helmut R. Salih,
Kathrin Rothfelder,
Dimitrios A. Tsakiris,
Jakob R. Passweg,
Pontus Lundberg,
Claudia Lengerke
Affiliations
Anna M. Paczulla
University of Basel and University Hospital Basel, Department of Biomedicine, Switzerland
Stephan Dirnhofer
University of Basel and University Hospital Basel, Department of Pathology, Switzerland
Martina Konantz
University of Basel and University Hospital Basel, Department of Biomedicine, Switzerland
Michael Medinger
University of Basel and University Hospital Basel, Clinic for Hematology, Switzerland
Helmut R. Salih
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tübingen, Department for Internal Medicine II, Tübingen, Germany;Department of Hematology and Oncology, Eberhard-Karls-University, Tübingen, Germany
Kathrin Rothfelder
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner site Tübingen, Department for Internal Medicine II, Tübingen, Germany;Department of Hematology and Oncology, Eberhard-Karls-University, Tübingen, Germany
Dimitrios A. Tsakiris
University of Basel and University Hospital Basel, Diagnostic Hematology, Switzerland
Jakob R. Passweg
University of Basel and University Hospital Basel, Clinic for Hematology, Switzerland
Pontus Lundberg
University of Basel and University Hospital Basel, Diagnostic Hematology, Switzerland
Claudia Lengerke
University of Basel and University Hospital Basel, Department of Biomedicine, Switzerland;University of Basel and University Hospital Basel, Clinic for Hematology, Switzerland;Department of Hematology and Oncology, Eberhard-Karls-University, Tübingen, Germany
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/IL2Rγnull mice (27.5±9.4 weeks) than did cells from intermediate-risk (21.9±9.4 weeks, P
