NOTE

🌱 created from: flt3_mutation_in_aml

types_of_flt3_mutations

FLT3 mutations, specifically FLT3-ITD (Internal Tandem Duplication) and FLT3-TKD (Tyrosine Kinase Domain), are significant in the context of acute myeloid leukemia (AML). Both mutations lead to constitutive activation of the FLT3 kinase, promoting cell proliferation and survival, but they differ in their prevalence, prognostic implications, and mechanisms of action.

Characteristics	FLT3-ITD	FLT3-TKD
Prevalence	25% of AML cases	7-10% of AML cases
Prognosis	Poorer prognosis, higher leukemic burden	Variable impact on prognosis, less clear
Mechanism	Longer protein product, altered signaling pathways	Point mutations, affecting kinase domain and drug binding
Clinical Impact	More aggressive disease course, poorer outcomes	More variable impact on prognosis
Resistance Mechanisms	Confer resistance through high leukemic burden	Alter drug-binding site, complicating treatment strategies
Treatment Considerations	Target for specific inhibitors, often necessitates more aggressive treatment	Role in treatment decisions still being clarified, particularly regarding interaction with FLT3-ITD

FLT3-ITD

Characteristics and Prevalence

• Prevalence: FLT3-ITD mutations are found in approximately 25% of AML cases, making them the most common FLT3 mutation[2].

• Prognosis: The presence of FLT3-ITD is associated with a higher leukemic burden and a poorer prognosis. Patients with this mutation often exhibit a higher total leukocyte count and blast percentage in peripheral blood, indicating more aggressive disease[1][2].

• Mechanism: FLT3-ITD mutations result in a longer protein product that alters the normal signaling pathways, leading to increased cell survival and proliferation. This mutation is a primary driver of AML and is linked to resistance to certain therapies[4].

FLT3-TKD

Characteristics and Prevalence

• Prevalence: FLT3-TKD mutations occur in about 7-10% of AML cases, making them less common than FLT3-ITD mutations[2][5].

• Prognosis: The prognostic significance of FLT3-TKD mutations is less clear compared to FLT3-ITD. While some studies suggest that they may confer a poorer outcome, the evidence is not as robust[2][5].

• Mechanism: TKD mutations typically involve point mutations that lead to changes in the kinase domain, affecting the binding and efficacy of FLT3 inhibitors. These mutations can also contribute to drug resistance, particularly when they occur alongside FLT3-ITD mutations, as seen in dual mutants[4].

Comparison of FLT3-ITD and FLT3-TKD

• Clinical Impact: FLT3-ITD mutations are generally associated with a more aggressive disease course and poorer outcomes, while FLT3-TKD mutations have a more variable impact on prognosis.

• Resistance Mechanisms: Both mutations can lead to resistance against FLT3 inhibitors, but the mechanisms differ. FLT3-ITD mutations are more likely to confer resistance through high leukemic burden, whereas TKD mutations can alter the drug-binding site, complicating treatment strategies[4][5].

• Treatment Considerations: Testing for FLT3 mutations is crucial for guiding treatment decisions. FLT3-ITD is a target for specific inhibitors, and its presence often necessitates more aggressive treatment approaches. In contrast, the role of FLT3-TKD in treatment decisions is still being clarified, particularly regarding its interaction with FLT3-ITD mutations[2][5].

In summary, while both FLT3-ITD and FLT3-TKD mutations are critical in AML, they differ significantly in their prevalence, clinical implications, and mechanisms of action, influencing treatment strategies and patient outcomes.

Citations: [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885130/ [2] https://www.nature.com/articles/s41375-018-0357-9 [3] https://www.sciencedirect.com/science/article/pii/S2468294221001301 [4] https://ashpublications.org/blood/article/105/9/3679/21247/FLT3-ITD-TKD-dual-mutants-associated-with-AML [5] https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.612880/full [6] https://ashpublications.org/blood/article/110/11/3486/75357/FLT3-ITD-but-Not-FLT3-TKD-Mutations-Have-Major [7] https://www.uncmedicalcenter.org/app/files/public/3695/pdf-medctr-mclendon-labs-flt3-and-npm1-gene-defects.pdf [8] https://www.researchgate.net/figure/Prognostic-impact-and-genetic-stability-of-FLT3-ITD-and-FLT3-TKD-mutations-in-AML-A-OS_fig7_260645239