TYROSINE KINASE ONCOGENESIS IN MYELOID LEUKEMIA

Dana-Farber Cancer Institute, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The long-term goals of this Program are to understand the pathogenesis of acute myeloid leukemias and use this information to develop novel therapeutic strategies to cure these disorders. A central hypothesis is that AML's are caused by multiple oncogenes that cooperate to cause leukemia. Thus, different leukemia oncogenes are likely to disrupt various cellular processes. An essential event is blocking differentiation, most likely by disrupting the transcription factor network that regulates myelopoiesis. The focus of this project is to understand the contribution of mutations in FLT3 to the pathogenesis of AML, and use this information to develop novel therapeutic strategies. FLT3 is a tyrosine kinase transmembrane receptor normally expressed in immature myeloid cells and required for proper development of hematopoietic stem cells, B cells, dendritic cells, and NK cells. Mutations in this receptor have been discovered in 20-30% of AMLs and are believed to cause constitutive activation of the receptor. Most of the mutations are in the juxtamembrane domain immediately inside the cell membrane, and involve in-frame, tandem, duplications of usually short stretches of DNA. In this project, we will determine the mechanism whereby these JM domain duplications activate the receptor, examine the mechanism of activation of a point mutation that also activates the receptor (D835Y), and compare the transforming functions of mutant FLT3 to those of another common tyrosine kinase oncogene of myeloid leukemias, BCR/ABL. Finally, small molecule kinase inhibitors are now available for both FLT3 and BCR/ABL and they will be studied to determine mechanisms of action on leukemic cells, modes of resistance, and opportunities for incorporation into novel combination chemotherapies. Successful completion of the studies proposed in this project will result in improved understanding of the pathogenesis of AML and the development of novel treatment strategies.