FLT3 in human hematologic malignancies.
FLT3, a member of the receptor tyrosine kinase (RTK) class III, is preferentially expressed on the surface of a high proportion of acute myeloid leukemia (AML) and B-lineage acute lymphocytic leukemia (ALL) cells in addition to hematopoietic stem cells, brain, placenta and liver. An interaction of FLT3 and its ligand has been shown to play an important role in the survival, proliferation and differentiation of not only normal hematopoetic cells but also leukemia cells. Mutations of the FLT3 gene was first reported as an internal tandem duplication (ITD) of the juxtamembrane (JM) domain-coding sequence, subsequently as a missense mutation of D835 within a kinase domain. ITD- and D835-mutations are essentially found in AML and their frequencies are approximately 20 and 6% of adults with AML, respectively. Thus, mutation of the FLT3 gene is so far the most frequent genetic alteration reported to be involved in AML. Several large-scale studies in well-documented patients published to date have demonstrated that ITD-mutation is strongly associated with leukocytosis and a poor prognosis. In this review, we summarize the clinical and biological significance of FLT3-mutations and discuss the possibility of targeting FLT3 kinase for the treatment of leukemia.
Kiyoi
Hitoshi
H
Department of Infectious Diseases, Nagoya University School of Medicine, Japan. kiyoi@med.nagoya-u.ac.jp
Naoe
Tomoki
T
D016227:Benzoquinones; D006801:Humans; D047029:Lactams, Macrocyclic; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011809:Quinones / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D017828:Rifabutin / Q000031:analogs & derivatives; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011518:Proto-Oncogene Proteins; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3