Modeling RUNX1-Associated Clonal Hematopoietic Disorders in Zebrafish
The balanced function of blood stem cells ensures normal production of blood cells. Individuals with inherited mutations in the RUNX1 gene have an increased lifetime risk of developing blood malignancies rising from the imbalance of these cells due to an abnormal clone. The clonal disorders result in ineffective production of blood cells and are on a spectrum from pre-leukemia, such as myelodysplastic syndromes (MDS), to acute myeloid leukemia (AML). For clonal disorders to initiate, genetic abnormalities in addition to RUNX1 are required.
We will model the process of leukemia initiation that is accompanied with expansion of an abnormal stem cell clone in zebrafish to better understand how the disease is established and how to treat it. We use a special technique of coloring blood stem cell clones and their progeny. The result is groups of colored blood cells, each representing cells originating from a same-colored stem cell clone. During normal hematopoiesis after labeling, blood cells are multicolored reflecting their baseline diversity.
Our model is ideal for studying takeover of an abnormal clone, namely dominance of one particular color in blood, as happens in MDS/AML. This will allow us to define the individual roles of specific RUNX1 mutations and secondary genetic abnormalities required for MDS/AML initiation. We will use zebrafish with established MDS/AML to screen a chemical library of compounds for reversal of abnormal mono-colored to normal multi-colored blood cell production, thus preventing progression to pre-leukemia or leukemia in healthy carriers of RUNX1 mutations.