Just as environmental damage reduces the diversity of species within an ecosystem, stresses on the hematopoietic system and its microenvironment such as chemotherapy, radiation or stem cell transplantation reduces the diversity of hematopoietic stem cells. This tends to select for stem cells with mutations that can lead to blood cancers. We want to understand how this selection occurs and find ways to mitigate this effect. To understand how the microenvironment shapes stem cell clonal evolution through periods of stress, we are using gain- and loss-of-function genetic techniques in the zebrafish coupled with lineage tracing tools and single cell RNA sequencing. This knowledge will be used to develop therapies aiming to prevent development of blood cancers after administration of chemotherapy or therapeutic radiation.
Clonal hematopoiesis is a condition where genetic mutations associated with blood cancers arise in blood stem cells. The frequency of clonal hematopoiesis increases with age and some patients with this condition progress to aggressive blood cancers. Yet we have little understanding of whom will progress or how this occurs. Recent data suggest that interactions with the stem cell microenvironment may play a role in selecting for blood stem cells with certain genetic mutations. We hypothesize that cxcl8 is expressed in stem cells with certain mutations, locally remodels the stem cell microenvironment and helps select for these mutant clones. We are using zebrafish genetics, microscopy and lineage tracing to understand how this occurs.
Zebrafish make an excellent model for cancer. In collaboration with others within the OSU Departments of Hematology and Medical Oncology we are developing models of pre-leukemia, AML, CLL and bile-duct cancer. These zebrafish models will be used to explore tumor-microenvironment interactions and as a platform for drug screens to identify novel anti-cancer agents.