Grant: Travel Awards - Institute Community Support

Acute Myeloid Leukemia (AML) is a type of blood cancer where primitive white blood cells multiply uncontrollably without maturing into functional white blood cells. It is caused by mutations in the DNA of these cells that affect genes involved in the control of cell proliferation and differentiation. Many genetic mutations have been shown to cause AML and certain genes, when mutated, confer a very low chance of cure for the patients. One such gene, named RUNX1, leads to resistance to current treatment options and to a mortality rate of more than 80%. The need for better therapeutic options is clear and we are tackling this problem by using a chemo-genomic approach. It combines detailed genetic information from patients and the response of their cells to drugs in vitro. By using this approach, we aim at identifying associations between defects in DNA and drugs that can kill the cells bearing these defects. More than defining these associations, we want to understand the biology governing them. In my PhD project, we found that RUNX1 mutations render cells more sensitive to glucocorticoids, a widely used anti-inflammatory drug that is not used in the treatment of AML patients. We are using this model to understand the mechanisms of resistance and sensitivity to glucocorticoids in AML. We created genetic modified cells from patients that carry a traceable marker in each gene of the human genome. We can use these mutant cells to perform large-scale screens, where we delete one gene at a time and expose the cells to the drugs. We then evaluate the effect of genes individually in the response to the drugs and pinpoint the important genes that make cells resistant or sensitive. By applying this methodology in patient-derived AML cells, we can identify new druggable targets that can potentiate the deadly effect of glucocorticoids in AML cells, and can be tested for combinatorial therapies to develop safer and more efficient therapies for poor outcome AML patients.