title: 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.
authors.affiliation: Department of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zheng
authors.forename: Donald
authors.initials: D
authors.lastname: Small
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008565:Membrane Proteins / Q000502:physiology; D022423:Myeloid Cells / Q000166:cytology / Q000502:physiology*; D051941:fms-Like Tyrosine Kinase 3 / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C084881:flt3 ligand protein; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3