Uncovering the Dysregulated RNA Binding Protein Network in Childhood Acute Myeloid Leukemia
Background: Genetic alterations and epigenetic mechanisms can alter the balance of normal blood development resulting in hematological malignancies. Acute myeloid leukemia represents approximately 20% of all childhood leukemias. Despite a better prognosis for childhood leukemia compared to adults, 30% of children eventually fail to respond to therapy. An altered differentiation program that is accompanied by uncontrolled cell growth defines these leukemias. Comprehensive genetic and epigenetic mapping of pediatric myeloid leukemias have resulted in a heterogeneous and complex picture that characterizes this disease. However, one feature that correlates with the most aggressive myeloid leukemias is the gain of a self-renewal program that resembles features found in the normal hematopoietic stem cell. Our recent studies have uncovered a dysregulated RNA binding protein network in leukemia stem cells
Project Goal: This proposal studies an RNA binding protein called SYNCRIP that is altered in myeloid leukemia. We have developed novel mouse genetic models in order to identify novel strategies for targeting the stem cell program in pediatric leukemias.
Project Update 2021: Our project focused on how an RNA binding protein called SYNCRIP RNA plays an important role in both normal and malignant blood cancer cells. Using a newly developed genetic model, we uncovered that this factor controls the ability for blood stem cells to resist stress during serial transplantation. Little is known about how the reserve stem is maintained and how its regulated. We find that RNA regulators can control blood stem cell control. Most excitingly, we found that SYNCRIP is required in leukemias driven by commonly mutated pediatric cancer drivers more than in normal blood cells. Mechanistically, we identify for the first time the global direct targets of SYNCRIP in normal and blood cancer cells. We find that SYNCRIP controls the ability of mRNAs to be made into proteins. These studies provide evidence that targeting SYNCRIP could be a novel strategy to eliminate leukemia cells. Our future studies will develop small molecules to block their activity as a potential new therapeutic target in myeloid leukemia.
