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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Paczulla Anna M., Dirnhofer Stephan, Konantz Martina, Medinger Michael, Salih Helmut R., Rothfelder Kathrin, Tsakiris Dimitrios A., Passweg Jakob R., Lundberg Pontus, Lengerke Claudia,
Project Role and molecular targets of the transcription factor EVI1 in lymphoblastic leukemia and blood stem cell development
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Original article (peer-reviewed)

Journal Haematologica
Volume (Issue) 102(5)
Page(s) 854 - 864
Title of proceedings Haematologica
DOI 10.3324/haematol.2016.153528

Open Access

Type of Open Access Publisher (Gold Open Access)


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<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.