Final Report Summary - HULSCTARGETING (Human leukemic stem cells: from identification towards targeting and eradication)
Leukemia represents a heterogeneous group of diseases that remain difficult to treat, but we now understand why current treatment options often fail. Leukemia, much like the normal hematopoietic system, is organized in a hierarchy with leukemic stem cells (LSCs) residing at the top. In contrast to their fast-cycling progeny, LSCs are relatively slow-cycling cells that often escape currently available chemotherapy and cause relapse of disease. The number of LSCs in a patient is usually very low, so the primary challenge is to identify these LSCs and develop better drugs to target them. A subsequent challenge is that multiple genetically distinct clones frequently co-exist in an individual leukemia patient. Since these clones carry specific sets of mutations in their DNA, they require their own specific drugs or therapeutic approaches. This is an important aspect that is not addressed by current treatment strategies. A final challenge is that cancer cells generally use similar pathways as normal cells to control processes such as cell proliferation and cell death. This makes it difficult to find therapeutic windows.
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.
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.