Mutant FLT3 signaling contributes to a block in myeloid differentiation

Abstract

FLT3 is a member of the class III receptor tyrosine kinase family and is primarily expressed on hematopoietic stem/progenitor cells. Somatic mutations of FLT3 involving internal tandem duplication (ITD) of the juxtamembrane domain or point mutations in the activation loop have been identified in approximately 17 - 34% and 7 - 9% of acute myeloid leukemia (AML) patients, respectively. The ITD mutations appear to activate the tyrosine kinase domain through receptor dimerization in a FLT3 ligand-independent manner. Constitutively activated FLT3 provides cells with proliferative and anti-apoptotic advantages and portends an especially poor prognosis for patients with this mutation. FLT3/ITD mutations also contribute to a block of myeloid differentiation. FLT3 tyrosine kinase inhibitors suppress the growth and induce apoptosis and differentiation of leukemia cells expressing FLT3/ITD mutants. 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.