This is the second blog post in the series of posts focused on the FLT3 gene, FLT3 gene mutations, and functional consequences linked to FLT3 gene mutations.
In the first post, I described the FLT3 gene and its role, and in this one, I will present the FLT3 mutations and the functional consequences of those mutations.
By the way, here are links to all three blog posts:
What Causes FLT3 Mutation(s)?
Mutations in genes can lead to changes in the protein that they encode if they are protein-coding genes, which further leads to changes in the functionality of that given protein. Functional changes in a protein can happen in different ways by becoming more or less active or inactive. These changes in protein function further cause or can be associated with specific conditions and diseases.
In the case of the FLT-3 gene, there is no single cause that has so far been identified as the leading cause of the FLT-3 gene mutations. Some of the researched possibilities as potential causes of mutations in the FLT-3 gene are smoking and exposure to chemicals like benzene. However, this is inconclusive, and more research is needed to establish the definitive cause [citation].
Are FLT3 Mutations Hereditary?
The most commonly investigated FLT-3 mutations are somatic and, as such, are not heritable, meaning can not be passed to the next generation. By the way, somatic cells are all body cells except for the sex cells, egg, and sperm. If you want to check the difference between somatic and germline mutation you can read my short blog post about somatic and germline mutations here.
What Is an FLT3 ITD Mutation? What Is FLT3 ITD? How Common Is FLT3 ITD?
The most commonly investigated FLT-3 mutations that affect the function of the FLT-3 gene are:
Internal Tandem Duplications (ITDs). ITDs cause constitutive activation of the kinase receptor. Constitutive activation is a situation where the kinase receptor is continuously active.
Tyrosine Kinase Domain (TKD) point mutations that are less frequent than ITDs [citation].
The FLT-3 ITD mutations occur in ~25% of all FLT-3 clinically tested cases having acute myeloid leukemia (AML) and are associated with a poorer prognosis compared to other types of AML.
The ITD mutations occur in the juxtamembrane domain and or TKD1 domain (part of the molecule) of the kinase and can vary in length and location on these domains. When these molecule domains are mutated, they cause constitutive activation of the kinase (the kinase cannot shut off). Because of this, these mutations are considered driver mutation and induces a high leukemic burden with poor prognosis [citation].
What Causes AML Leukemia?
AML leukemia is a type of leukemia (cancer of blood cells) that affects the cells of the myeloid lineage in the bone marrow. Acute leukemia means that the disease develops rapidly and has a sudden onset. These cells are stem cells that give rise to several mature cells of the blood: red blood cells, white blood cells, and platelets. AML leukemia occurs when these cells harbor genetic mutations, such as FLT-3 [citation].
What Is FLT3 TKD Mutation?
FLT-3 point TKD mutations are small mutations occurring in ~7 to 10% of clinical cases. They cause constitutive activation of the kinase. The prognostic significance of TKD mutations is not well defined, so it cannot be said with confidence whether it confers a better or worse prognosis of survival [citation, citation].
What Is the FLT3 ITD Ratio? How Is the FLT3 ITD Ratio Calculated?
The allelic ratio measures how many gene alleles (forms of the same gene, inherited one from each parent) are mutated or wild-type. A ratio of mutant to wild-type alleles is calculated by dividing the mutant alleles detected by the wild-type allele detected and is not equivalent to mutant allele frequency or fraction (the percentage or fraction of mutant alleles within all of the alleles present in a given sample) [citation].
What Kind of Genetic Tests Are There for FLT3-Related AML Mutations?
FLT-3 mutations can be detected with molecular methods such as:
PCR fragment analysis
Sanger sequencing, and
Next-Generation Sequencing (NGS) [citation].
Molecular tests can be performed from peripheral blood, bone marrow, or tissue biopsy.
What Is FLT3-Positive AML?
Here, I refer to the result of the LeukoStrat® CDx FLT3 Mutation Assay. In that case, the FLT-3 positive mutation means that either the FLT-3 internal tandem duplication mutation and/or tyrosine kinase domain (TKD) point mutations were detected. This mutation is associated with a high leukemic burden and increased disease relapse, poor disease prognosis, and disease management [citation]. Approximately 30% of newly diagnosed AML patients harbor an FLT-3 mutation [citation].
What Does FLT3 Negative Mean?
Same as above, here I refer to the result of the LeukoStrat® CDx FLT3 Mutation Assay. In that case, the FLT-3 negative means that neither internal tandem duplication nor tyrosine kinase domain (TKD) point mutations were found in the tested sample. This, however, does not mean that the disease is not present.
What Are FLT3 Inhibitors? What Is an FLT3 Inhibitor? How Do FLT3 Inhibitors Work?
FLT-3 inhibitors are drugs used to inhibit or abolish FLT-3 kinase activity, which is constitutively active in FLT-3 positive AML cases.
Currently, FLT3 inhibitors can be divided into:
Type I FLT-3 inhibitors are active against both ITD and TKD mutations. Such an example is midostaurin, which can be used with other agents. I also wrote a short article about midostaurin that you can check here.
Type II FLT-3 inhibitors are only active against FLT-3 ITD mutation. Since they are more specific, there is less toxicity associated with their use. An example is sorafenib which is very efficient in combination with anthracycline/cytarabine.
Second-generation FLT-3 inhibitors are also used, such as quizartinib and gilteritinib. These treatments are maintained until the first disease relapse [citation].
If you are interested in the details regarding FLT3 inhibitors, check the third blog post in this series that focuses on FLT-3 mutation testing and FLT-3 inhibitors:
If you would like to read more about the FLT3 gene and its role, please check the first blog post in this series: