Role of FLT3 in leukemia.
FLT3 is the most frequently mutated gene in cases of acute myelogenous leukemia (AML). About 30 to 35% of patients have either internal tandem duplications (ITDs) in the juxtamembrane domain or mutations in the activating loop of FLT3. FLT3 mutations occur in a broad spectrum of FAB subtypes in adult and pediatric AML and are particularly common in acute promyelocytic leukemia (APL). FLT3 mutations confer a poor prognosis in most retrospective studies. The consequence of either FLT3-ITD or activating loop mutations, which occur predominantly at position D835, is constitutive activation of the tyrosine kinase; FLT3 mutants confer factor-independent growth to Ba/F3 and 32D cells and activate similar transduction pathways as the native receptor in response to ligand, including the STAT, RAS/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3; kinase (PI3K)/AKT pathways. Injection of FLT3-ITD transformed cells, such as Ba/F3 or 32D, into syngeneic recipient mice results in a leukemia-like syndrome, and expression in primary murine bone marrow cells in a retroviral transduction assay results in a myeloproliferative disorder. Mutations that abrogate FLT3 kinase activity result in loss of transforming properties in these assays. Further, FLT3-selective inhibitors impair transformation of primary AML cells that harbor these mutations, and also inhibit FLT3 transformed hematopoietic cell lines, and leukemias induced by activated FLT3 mutants in murine models. Collectively, these data indicate that FLT3 may be a viable therapeutic target for treatment of AML.
Gilliland
D Gary
DG
Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. james_griffin@dfci.harvard.edu
Griffin
James D
JD
D000208:Acute Disease; D000818:Animals; D002471:Cell Transformation, Neoplastic; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3
D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3