FMS-like tyrosine kinase 3, or FLT3, signaling is a communication pathway that helps regulate the development of cells. It is a type of receptor tyrosine kinase, which functions like an antenna on the cell surface. This receptor receives external signals that instruct the cell on how to behave, particularly when to grow, multiply, and mature.
The FLT3 signaling pathway is especially active in the hematopoietic system, which is responsible for creating new blood cells. It helps control the production of various types of blood cells from a common origin.
Function of Normal FLT3 Signaling
The primary role of FLT3 signaling is to govern hematopoiesis, the process of forming new blood cells from hematopoietic stem cells. These stem cells, located in the bone marrow, have the potential to develop into all the different types of blood cells. The FLT3 receptor is prominently found on the surface of these early, unspecialized blood cells.
The signaling process begins when a specific molecule, known as the FLT3 ligand, binds to the FLT3 receptor. This binding event causes two FLT3 receptors to pair up, or dimerize, which activates their internal kinase function. This activation triggers a cascade of chemical reactions inside the cell, a process called autophosphorylation, where phosphate groups are added to the receptor itself. This creates docking sites for other proteins.
Once activated, the receptor initiates several downstream signaling pathways, including the PI3K/Akt and MAPK cascades, which transmit the growth signal from the cell surface to the nucleus. This network of signals promotes the survival of hematopoietic progenitor cells, encourages their proliferation, and guides their differentiation into more specialized blood cells.
FLT3 Mutations and Cancer Development
Genetic mutations can disrupt the carefully regulated process of FLT3 signaling, leading to uncontrolled cell growth. When the gene that provides the instructions for making the FLT3 protein is altered, it can cause the receptor to become permanently “switched on.” This means the receptor constantly sends growth signals, even in the absence of the FLT3 ligand. This persistent signaling is a driver in the development of certain cancers, particularly Acute Myeloid Leukemia (AML).
Two main types of mutations are commonly found in the FLT3 gene. The first is an internal tandem duplication (FLT3-ITD). This mutation involves the insertion of a duplicated segment of the gene’s DNA into the receptor’s structure, which disrupts its normal shape and function, causing it to be constantly active. The second type is a point mutation in the tyrosine kinase domain (FLT3-TKD), which also locks the receptor in an active state. Both mutations lead to the constitutive activation of downstream signaling pathways like the JAK-STAT and RAS-MAPK pathways.
FLT3 mutations are among the most frequent genetic alterations identified in patients with AML. These mutations are linked with more aggressive forms of the disease and are often associated with a higher count of leukemia cells at diagnosis. The relentless growth signals produced by the mutated FLT3 receptors give the cancerous cells a survival advantage, allowing them to multiply rapidly and overwhelm the normal blood-forming cells in the bone marrow.
The mutated FLT3 protein not only promotes cell proliferation but also suppresses apoptosis, the natural process of programmed cell death. For instance, FLT3-ITD signaling can lead to the phosphorylation and subsequent inactivation of the FOXO3a transcription factor. This prevents the expression of genes that would normally cause a damaged or excessively proliferating cell to self-destruct, further contributing to the accumulation of malignant cells.
Targeting FLT3 in Medical Treatments
The discovery of FLT3’s role in driving cancer has led to the development of targeted therapies designed to block its activity. These drugs, known as FLT3 inhibitors, are engineered to fit into the FLT3 receptor and prevent it from sending continuous growth signals. By inhibiting the faulty receptor, these treatments can slow down the proliferation of cancer cells and, in some cases, induce their death.
FLT3 inhibitors are often used in combination with standard chemotherapy to improve patient outcomes. The first generation of these inhibitors demonstrated the potential of this approach, but newer, second-generation inhibitors have been developed to be more potent and specific. Examples of these drugs include midostaurin, a first-generation inhibitor, and gilteritinib, a second-generation inhibitor.
These targeted drugs work by competing with the energy source that the kinase domain of the receptor uses to function. By blocking this, the entire downstream signaling cascade that promotes cell growth and survival is shut down. This specific action makes targeted therapy different from traditional chemotherapy, which affects all rapidly dividing cells, both cancerous and healthy.
However, a challenge in using these therapies is the potential for the cancer cells to develop resistance. Over time, new mutations can arise in the FLT3 gene or in other signaling pathways that allow the cancer to bypass the effects of the inhibitor. This has prompted ongoing research into the next generation of inhibitors and combination strategies to overcome resistance and provide more durable responses for patients.
Diagnostic Testing for FLT3 Mutations
Identifying the presence of FLT3 mutations is a standard part of the diagnostic process for individuals newly diagnosed with AML. The results of these tests help oncologists decide if a targeted FLT3 inhibitor should be included in the treatment regimen.
To perform the test, a sample of the patient’s blood or bone marrow is collected. From this sample, DNA is extracted from the leukemic cells. Laboratory specialists then use molecular techniques to analyze the FLT3 gene for the presence of ITD or TKD mutations. Common methods for this analysis include polymerase chain reaction (PCR) and next-generation sequencing (NGS).
PCR is a technique that can amplify a specific segment of DNA, making it easier to detect the presence of an ITD mutation, which changes the length of the DNA fragment. NGS is a more comprehensive method that can read the exact sequence of the DNA, allowing for the detection of both ITD and various TKD point mutations. The information gained from these diagnostic tests is fundamental to personalizing cancer treatment.