Investigating Downstream Molecular Pathways of FLT3 in Acute Myeloid Leukemia: Unraveling Molecular Mechanisms and Therapeutic Potentials

Acute myeloid leukemia (AML) stands as the second most prevalent form of leukemia, characterized by the rapid proliferation of immature blood cells within the myeloid lineage. The most frequently mutated gene in AML is FLT3, responsible for encoding a receptor tyrosine kinase—a signaling protein normally tasked with regulating hematopoiesis. Oncogenic variants of FLT3, featuring an internal tandem duplication (ITD), sustain continuous signaling, promoting cell survival, proliferation. The presence of FLT3-ITD mutations in AML correlates with a bleak prognosis and overall survival. While the intricacies of FLT3 signaling in health and disease are only partially understood, the development of resistance to FLT3-targeting drugs poses a significant challenge, undermining effective treatment. In response to this issue, our approach involves elucidating the signaling mechanisms and network of oncogenic FLT3-ITD. Our research plan encompasses various objectives: Aim I: Identifying novel signaling molecules downstream of FLT3 and examining their role in FLT3-ITD-mediated transformation; Aim II: Conducting in silico docking studies to identify novel small molecule inhibitors of FLT3; and Aim III: Establishing a resource of patient-derived xenografts of AML cells.