Surface expression of FLT3 protein was correlated with high percentage of bone marrow blasts and with FLT3 mRNA expression (r=0.366, P<0.001) in acute leukemia.
In order to further analyze this phenomenon, we investigated the localization of FLT3, a subclass III receptor tyrosine kinase frequently mutated in leukemia.
Taken together, these experiments establish that the FLT3/ITD mutations are present in leukemia stem cells, and that FLT3 inhibitors may have activity against these cells.
Therefore, FLT3 is a therapeutic target and inhibition of FLT3 tyrosine kinase activity may provide a new approach in the treatment of leukemia carrying these mutations.
An improved understanding of how FLT-3 interacts with its ligand, as well as how FLT-3 activating mutations are able to trigger downstream intracellular signaling pathways, will provide greater insight to how small molecule inhibitors may best be utilized and combined with established chemotherapeutic drugs for the management of patients with high-risk acute leukemia.
These data suggest that activating mutations of Flt3 may disrupt transcriptional repressor function resulting in aberrant gene regulation and abnormal leukemia cell growth.