Identifying novel targets for directed therapy against acute leukemia by uncovering the molecular details of FLT3 signaling

Acute myeloid leukemia (AML) is the second most common type of leukemia, characterized by a rapid expansion of immature blood cells of the myeloid lineage.

The most commonly mutated gene in AML is FLT3, which encodes a receptor tyrosine kinase and it is a signaling protein normally involved in regulating hematopoiesis.

Oncogenic forms of FLT3, harboring an internal tandem duplication (ITD), signal constitutively, driving cell survival and proliferation, which correlates with poor prognosis and poor overall survival. The details of FLT3 signaling in health and disease are not well understood. Resistance to FLT3-targeting drugs  frequently develops, compromising effective treatment.

To address that, we will delinate the signaing mechanisms and network of wild-type FLT3 and oncogenic FLT3-ITD.

Using cell and animal models, we will uncover the roles of membrane-bound and soluble FL, the FLT3 ligand (Aims I, months 1-48); identify signaling molecules downstream of FLT3 (Aim II, months 1-48); investigate the function of nuclear FLT3 (Aim III, months 1-24); and develop an improved system for anti-FLT3 drug screening based on cells derived from primary AML patient material (Aim IV, months 25-60).

In the short-tem, this project will reveal molecular details of FLT3 cell function. In the long-term, the finding will inform the development of effective anti-AML drugs.