A Humanized Ossicle-niche Xenotransplantation Model Enables Improved Human Leukemic Engraftment

Xenotransplantation models provide powerful tools for the investigation of human normal and malignant hematopoiesis. However, current models do not extensively recapitulate human bone marrow (BM) microenvironment components and exhibit limited engraftment of many human leukemias and other disorders. Here, we describe a xenotransplantation model bearing subcutaneous humanized ossicles with an accessible BM microenvironment formed by in situ differentiation of human BM-derived mesenchymal stromal cells. In these humanized ossicles, we observed robust engraftment of normal human hematopoietic stem and progenitor cells, and detected extensive engraftment of diverse primary acute myeloid leukemia samples at levels much greater than in unmanipulated mice. Direct intraossicle transplantation accelerated engraftment and resulted in substantially higher leukemia-initiating cell frequencies. We also observed robust engraftment of acute promyelocytic leukemia and myelofibrosis leading to the identification of leukemia-initiating cells in hematopoietic stem cells in myelofibrosis. This humanized ossicle xenotransplantation approach provides a novel system to model human hematologic disease.