Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice.
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/IL2Rγnullmice (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 allowsin vivomouse 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.
University of Basel and University Hospital Basel, Department of Biomedicine, Switzerland.
Anna M
AM
Paczulla
University of Basel and University Hospital Basel, Department of Pathology, Switzerland.
Stephan
S
Dirnhofer
University of Basel and University Hospital Basel, Department of Biomedicine, Switzerland.
Martina
M
Konantz
University of Basel and University Hospital Basel, Clinic for Hematology, Switzerland.
Michael
M
Medinger
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.
Helmut R
HR
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
K
Rothfelder
University of Basel and University Hospital Basel, Diagnostic Hematology, Switzerland.
Dimitrios A
DA
Tsakiris
University of Basel and University Hospital Basel, Clinic for Hematology, Switzerland.
Jakob R
JR
Passweg
University of Basel and University Hospital Basel, Diagnostic Hematology, Switzerland.
Pontus
P
Lundberg
University of Basel and University Hospital Basel, Department of Biomedicine, Switzerland claudia.lengerke@unibas.ch.|University of Basel and University Hospital Basel, Clinic for Hematology, Switzerland.|Department of Hematology and Oncology, Eberhard-Karls-University, Tübingen, Germany.
Claudia
C
Lengerke
D000208:Acute Disease; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic; D006085:Graft Survival / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000379:methods*; D013997:Time Factors; D014183:Transplantation, Heterologous
D018952:Antigens, CD34