The FLT3 gene provides the instructions for making a protein called fms-like tyrosine kinase 3, often referred to simply as FLT3. This gene is involved in the healthy development and regulation of various blood cell types within the body. The FLT3 protein itself is part of a larger family of proteins known as receptor tyrosine kinases, which play a role in transmitting signals into cells.
The Normal Function of FLT3
The FLT3 protein functions as a receptor tyrosine kinase, meaning it resides on the surface of certain cells and acts like a specialized antenna. Its primary location is on hematopoietic progenitor cells, which are early blood cells responsible for forming different mature blood cell types. When a specific protein called the FLT3 ligand binds to this receptor, it activates the FLT3 protein.
This activation initiates a cascade of signals inside the cell. These internal signals direct various cellular processes, including cell growth, division, and survival. The proper functioning of the FLT3 protein is thus involved in the regulated proliferation and maturation of blood-forming cells, ensuring the body maintains a healthy supply of different blood components.
FLT3 Mutations in Leukemia
When the FLT3 gene undergoes a mutation, its normal signaling mechanism can become disrupted. In acute myeloid leukemia (AML), a type of blood cancer, FLT3 mutations are among the most common genetic changes, occurring in approximately one-third of newly diagnosed adult patients. These mutations cause the FLT3 receptor to become “constitutively active,” meaning it is continuously turned on, even without the presence of its normal ligand.
Two primary types of FLT3 mutations are observed in AML: Internal Tandem Duplications (ITD) and Tyrosine Kinase Domain (TKD) point mutations. FLT3-ITD mutations involve a segment of DNA being copied and inserted directly next to the original sequence within the gene. These duplications primarily affect the juxtamembrane domain of the FLT3 protein, disrupting its normal regulatory function.
FLT3-TKD mutations, less frequent than ITD, involve a single change in the protein’s building blocks within its tyrosine kinase domain, often at position 835 (Asp835Tyr). Both ITD and TKD mutations lead to the FLT3 receptor being stuck in an “on” position, constantly sending growth signals. This uncontrolled signaling results in the rapid and unregulated production of immature white blood cells, known as leukemic blasts, which is a hallmark of AML.
Testing for FLT3 Mutations
Identifying FLT3 mutations is a standard part of diagnosing and managing acute myeloid leukemia. Doctors typically obtain samples for testing from either a bone marrow biopsy or a blood draw. Bone marrow is often the preferred specimen for FLT3 mutation assessment, although peripheral blood is acceptable if sufficient leukemic cells are present.
Once collected, laboratory techniques are employed to detect specific genetic alterations within the FLT3 gene. Polymerase Chain Reaction (PCR) is a common method, often used as PCR-fragment analysis for ITD mutations and PCR-RFLP for TKD mutations. Next-Generation Sequencing (NGS) is another advanced technique that can detect these mutations, providing comprehensive genetic information. These tests aim to identify the presence and type of FLT3 mutation, with a detection sensitivity that can identify mutant cells when they comprise as little as 1% to 10% of the sample.
Targeted Therapies for FLT3-Mutated Cancers
The discovery of FLT3 mutations led to the development of targeted therapies specifically designed to counteract their effects. These drugs, known as FLT3 inhibitors, work by blocking the constant, aberrant signaling pathway caused by the mutated FLT3 protein. By doing so, they aim to slow or halt the uncontrolled proliferation of leukemic cells while minimizing harm to healthy cells.
Approved FLT3 inhibitors include midostaurin, gilteritinib, and quizartinib, each working to specifically interfere with the overactive FLT3 receptor. Midostaurin, for instance, was the first FLT3 inhibitor approved for use in newly diagnosed adults with FLT3-mutated AML and is often administered alongside standard chemotherapy. Gilteritinib is another inhibitor commonly used for patients whose AML has either not responded to earlier treatments or has returned after initial therapy. These targeted agents represent an advancement in personalizing treatment approaches for individuals with FLT3-mutated AML.
Prognostic Implications
Historically, the presence of certain FLT3 mutations, particularly FLT3-ITD, has been associated with a less favorable outlook for patients with acute myeloid leukemia. This specific mutation has been linked to a higher risk of the disease returning after treatment and a more aggressive form of AML. The impact on prognosis can vary depending on factors such as the amount of mutated gene present and the presence of other co-occurring genetic changes.
The landscape of AML treatment has evolved significantly with the introduction of FLT3 inhibitors. The development of these specific drugs has led to notable improvements in managing patients with FLT3-mutated AML. While FLT3-ITD mutations still indicate a higher risk, the availability of targeted therapies has provided new avenues for treatment, contributing to better patient outcomes and altering the historical prognostic outlook for this subtype of leukemia.