- Anna M. Paczulla1,
- Stephan Dirnhofer2,
- Martina Konantz1,
- Michael Medinger3,
- Helmut R. Salih4,
- Kathrin Rothfelder5,
- Dimitrios A. Tsakiris6,
- Jakob R. Passweg3,
- Pontus Lundberg6 and
- Claudia Lengerke1,*
- 1 University of Basel and University Hospital Basel, Department of Biomedicine, Basel, Switzerland;
- 2 University of Basel and University Hospital Basel, Department of Pathology, Basel, Switzerland;
- 3 University of Basel and University Hospital Basel, Clinic for Hematology, Basel, Switzerland;
- 4 Clinical Collaboration Unit Translational Immunology (DKTK and DKFZ), Tuebingen, Germany;
- 5 Department of Hematology and Oncology, Eberhard-Karls-University, Tuebingen, Germany;
- 6 University of Basel and University Hospital Basel, Diagnostic Hematology, Basel, Switzerland
- ↵* Corresponding author; email:
Repopulation of immunodeficient mice remains the primary method to func-tionally assess human acute myeloid leukemia. Published data report en-graftment of ~40-66% of cases, mostly belonging to intermediate or poor risk subtypes. Here we report that extending follow-up beyond the standard analysis end-points of 10 to 16 weeks post-transplantation permitted leukemic engraftment from nearly every xenotransplanted acute myeloid leukemia case (18/19, ~95%). Xenogeneic leukemic cells showed conserved immune phenotypes and genetic signatures when compared to corresponding pre-transplant cells, and were furthermore 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 on showed robust engraftment (61%, termed long latency engrafters), indicating that leukemic cells can persist over months at undetectable levels without losing disease-initiating properties. Favorable risk leukemic cells required longer time to be-come detectable in NOD/SCID/IL2Rγnull mice (27.5±9.4 weeks) than intermediate (21.9±9.4 weeks, p<0.01) or adverse risk subtypes (17±7.6 weeks; p<0.0001), explaining why the engraftment of first was missed with previous protocols. Mechanistically, leukemic cells engrafting with prolonged latency showed inferior homing to the BM. 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. Together, we provide a model that allows in vivo mouse studies with a wide range of molecular acute myeloid leukemia subtypes previously considered non-engraftable, thus enabling novel insights on leukemogenesis.
- Received July 28, 2016.
- Accepted February 6, 2017.
- Copyright © 2017, Ferrata Storti Foundation