Final Report Summary - HULSCTARGETING (Human leukemic stem cells: from identification towards targeting and eradication)
To take a real step forward in cancer treatment, these challenges must be tackled. First, we have been able to establish a humanized niche xenograft mouse leukemic mouse clinic. By implanting ceramic scaffolds coated with human mesenchymal stromal cells (MSCs) into immune deficient mice we mimic the human bone marrow niche. Thus, we have established a human leukemia xenograft mouse model in which a large cohort of patient samples successfully engrafted covering all important genetic and risk subgroups. We find that by providing a humanized environment stem cell self-renewal properties are better maintained as determined by serial transplantation assays and genome-wide transcriptome studies, and less clonal drift is observed as determined by exome sequencing. The human leukemia xenograft mouse models that we have established here will serve as an excellent resource for future studies aimed at exploring novel therapeutic approaches. Furthermore, by making use of these models, we have been able to identify essential signaling networks and epigenetic machinery in normal and leukemic stem cell populations. By targeting some of these we efficiently impaired leukemia development in vitro as well as in vivo. Finally, we have gained considerable insight into the unique repertoire of plasma membrane proteins in LSCs and their subclones, which we can now prospectively isolate and study.