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Role of FLT3 in leukemia
D Gary Gilliland1, James D Griffin
1Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. james_griffin@dfci.harvard.edu
Abstract:
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.
Insights
FLT3 mutations are common in acute myelogenous leukemia (AML) and linked to poor prognosis. Targeting FLT3 kinase activity shows promise for treating AML patients with these mutations.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- FMS-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myelogenous leukemia (AML).
- Mutations, including internal tandem duplications (ITDs) and activating loop mutations, occur in 30-35% of AML patients.
- FLT3 mutations are associated with a poor prognosis across various AML subtypes.
Purpose of the Study:
- To investigate the functional consequences of FLT3 mutations in AML.
- To evaluate the therapeutic potential of targeting FLT3 in AML.
Main Methods:
- Analysis of FLT3 mutation types and their prevalence in AML.
- Functional assays using cell lines (Ba/F3, 32D) and murine models to assess the transforming properties of FLT3 mutants.
- Evaluation of FLT3-selective inhibitors in preclinical AML models.
Main Results:
- FLT3 mutations lead to constitutive tyrosine kinase activation, promoting factor-independent cell growth.
- FLT3 mutants activate key signaling pathways, including STAT, RAS/MAPK, and PI3K/AKT.
- FLT3-ITD expression induces leukemia-like syndromes in mice and myeloproliferative disorders in bone marrow cells.
- Inhibition of FLT3 kinase activity abrogates transforming properties and impairs AML cell transformation.
Conclusions:
- Constitutively active FLT3 mutants drive leukemogenesis.
- FLT3 kinase is a critical mediator of AML.
- FLT3 represents a viable therapeutic target for AML treatment.
