1. Overview
FLT3 (FMS-like tyrosine kinase 3), also known as CD135 or fetal liver kinase-2 (Flk2), is a gene that encodes a receptor-type tyrosine kinase involved in the formation, growth, and differentiation of hematopoietic cells. The FLT3 protein plays a key role in normal blood cell development by regulating cell survival, proliferation, and maturation.
Mutations in the FLT3 gene result in an overactive receptor, leading to uncontrolled signaling and excessive production of immature white blood cells. FLT3 mutations represent one of the most common genetic alterations observed in acute myeloid leukemia (AML).
2. Symptoms
FLT3 gene mutations do not directly cause symptoms; clinical manifestations arise from the underlying hematologic malignancy. Patients with FLT3-mutated leukemia may present with symptoms related to bone marrow failure, such as fatigue, anemia, recurrent infections, bleeding tendencies, and leukocytosis.
The disease is often aggressive, with a high burden of blast cells in peripheral blood and bone marrow, leading to rapid clinical progression if untreated.
3. Causes
FLT3 mutations occur due to genetic alterations affecting the receptor tyrosine kinase domain. The two most common mutation types include internal tandem duplications (ITD) and tyrosine kinase domain (TKD) point mutations, particularly at residues D835/I836.
These mutations cause constitutive activation of the FLT3 receptor independent of ligand binding, resulting in persistent downstream signaling that promotes leukemic cell proliferation, survival, and resistance to apoptosis. FLT3 mutations are typically somatic and acquired rather than inherited.
4. Risk Factors
FLT3 gene mutations are most frequently associated with acute myeloid leukemia and acute blastic (undifferentiated) leukemia. Presence of an FLT3 mutation is strongly associated with leukocytosis, increased blast percentage in blood and bone marrow, high tumor burden, and poor clinical outcomes.
FLT3-ITD mutations are linked with higher relapse rates and inferior prognosis, while FLT3-TKD mutations are associated with specific cytogenetic abnormalities. In myelodysplastic syndromes (MDS), detection of an FLT3 mutation may indicate progression toward AML. Pediatric AML cases with FLT3 mutations also show prognostic significance, guiding risk stratification and treatment decisions.
5. Prevention and Clinical Management
FLT3 mutation testing is an essential diagnostic and prognostic tool in patients with suspected or confirmed acute leukemia. Testing is indicated primarily in acute myeloblastic leukemia and acute blastic leukemia to assess prognosis and guide therapy selection.
Detection methods include PCR-based assays followed by agarose gel electrophoresis, fragment analysis using capillary electrophoresis, and next-generation sequencing (NGS). Real-time PCR assays are commonly used to detect FLT3-ITD and FLT3-TKD mutations in genomic DNA extracted from mononuclear cells.
Samples can be collected from either peripheral blood or bone marrow. Blood or marrow aspirates are collected in EDTA, heparin, or ACD tubes, with a minimum sample volume of 1.0 mL required for analysis.
Prognostically, FLT3 mutation status is a key factor in AML risk classification. FLT3 mutations are associated with poor prognosis, high relapse risk, and disease progression. Changes in FLT3 mutation status during follow-up may indicate disease evolution, relapse, or treatment resistance.
Targeted therapy has emerged as a major clinical application of FLT3 mutation testing. First-generation FLT3 inhibitors, including midostaurin, sorafenib, lestaurtinib, tandutinib, and sunitinib, showed limited efficacy. Second-generation FLT3 inhibitors, particularly gilteritinib, demonstrate higher selectivity and potency. Gilteritinib therapy has been shown to significantly improve overall survival compared to conventional chemotherapy in relapsed or refractory FLT3-mutated AML.
Overall, FLT3 mutation analysis plays a crucial role in diagnosis, prognostication, therapeutic decision-making, and disease monitoring in acute leukemia.
