Structural Studies of Flt3 Activation and Inhibition in AML

Fms-like tyrosine kinase-3 (Flt3) and its ligand (FL) playa critical role in the normal maintanence and differentiation of multipotent hematopoietic progenitor cells. Significant interest in the receptor tyrosine kinase Flt3 is due to its close association with both AML and ALL. Aberrant Flt3 expression is seen in virtually all leukemic blasts in both AML and ALL. Furthermore, mutations in Flt3 are observed in 35-40% of AML patients and are associated with a poor prognosis. Recently, additional mutations have been detected in the extracellular portion of Flt3, representing approximately 5% of AML patients. This work focuses on understanding the normal function and signaling of Flt3 as well as defining new means of inhibiting its activity in leukemia. Neuropilin is a cell surface receptor involved in angiogenesis and axon guidance. Neuropilin has long been appreciated to play a stimulatory role in angiogenesis, a process critical for growth of solid tumors. Recent evidence has demonstrated a role for Nrp in hematological malignancies. Nrp overexpression is observed in both multiple myeloma and acute myeloid leukemia and, in the later case, is associated with significantly reduced survival. This project seeks to define the fundamental mechanisms of activation of neuropilin as well as novel means of inhibition.