Sir Henry Wellcome Fellow University of Oxford OXFORD, England, United Kingdom
Abstract: Blood cancers remain amongst the top ten most common cancers in adults, and are the most common cancers affecting children. Many blood cancers remain untreatable as there are significant challenges in modelling the bone marrow in the context of disease. For example, it is difficult to culture and expand primary patient cells from a number of incurable blood cancers (e.g. multiple myeloma), limiting efforts to identify and validate new treatments for these diseases. The bone marrow microenvironment, comprised of a rich milieu of stromal cells and specialist vasculature, is heavily involved in disease initiation and progression. This contributes to acquired resistance to treatments. Models that capture this complexity are therefore required to meaningfully translate fundamental research.
Similarly, mouse models often poorly capture hallmarks of human disease, and humanised PDX transplant models remain subject to huge variability. There remains a need for scalable, species specific models of this organ to enable not only the culture of primary patient material ex vivo, but to facilitate the identification and validation of new therapeutic targets.
We recently published the first human induced pluripotent stem cell (hiPSC) derived bone marrow organoid system which captures both stromal and haematopoeitic lineages, and the specialist vascular architecture of the central bone marrow. We show a high degree of homology to native human tissues, and importantly, demonstrate the utility of this model as a platform for precision medicine using patient cells. We demonstrate that CD34+ cells from patients with myelofibrosis induce a remodelling of our organoid system that reconstitutes hallmarks of the incurable pathology and enables the screening of potential therapies at scale using primary patient material.
