Flt3, also known as FMS-like tyrosine kinase 3, is a receptor tyrosine kinase almost exclusively expressed in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of Flt3 leads to autophosphorylation and initiation of signal transduction cascades like STAT5, MAPK and AKT, mediating cell survival, proliferation, and differentiation of hematopoietic progenitor cells [4,5].

Mutations in the Flt3 gene are the most frequent genetic alteration in acute myeloid leukemia (AML), occurring in approximately 30% of all AML cases. The two major types are internal tandem duplication (ITD) in the juxtamembrane domain and point mutations or deletions in the tyrosine kinase domain (TKD). Flt3-ITD is the most common, present in about 25% of AML cases, associated with high leukemic burden, increased relapse, and poor prognosis. Flt3-TKD has a lower incidence (about 7-10% of cases), and its prognostic value is uncertain. Clonal evolution of Flt3 mutational status occurs during the disease. First-generation Flt3 inhibitors are broad-spectrum, while next-generation ones are more specific, but resistance to these inhibitors remains a challenge [1,2,3,4,7,8].

In conclusion, Flt3 is crucial for normal hematopoietic cell function through its signaling pathways. In AML, Flt3 mutations, especially Flt3-ITD, play a significant role in disease progression and prognosis. Understanding Flt3 through genetic models could potentially lead to better targeted therapies for AML patients. The development and use of Flt3 inhibitors, despite the resistance challenges, have already changed the treatment landscape for Flt3-mutated AML [1,2,3,4,6,7,8].

References:

1. Daver, Naval, Schlenk, Richard F, Russell, Nigel H, Levis, Mark J. 2019. Targeting FLT3 mutations in AML: review of current knowledge and evidence. In Leukemia, 33, 299-312. doi:10.1038/s41375-018-0357-9. https://pubmed.ncbi.nlm.nih.gov/30651634/

2. Kennedy, Vanessa E, Smith, Catherine C. 2020. FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies. In Frontiers in oncology, 10, 612880. doi:10.3389/fonc.2020.612880. https://pubmed.ncbi.nlm.nih.gov/33425766/

3. Negotei, Cristina, Colita, Andrei, Mitu, Iuliana, Stanca, Oana, Berbec, Nicoleta Mariana. 2023. A Review of FLT3 Kinase Inhibitors in AML. In Journal of clinical medicine, 12, . doi:10.3390/jcm12206429. https://pubmed.ncbi.nlm.nih.gov/37892567/

4. Kiyoi, Hitoshi, Kawashima, Naomi, Ishikawa, Yuichi. 2019. FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development. In Cancer science, 111, 312-322. doi:10.1111/cas.14274. https://pubmed.ncbi.nlm.nih.gov/31821677/

5. Kazi, Julhash U, Rönnstrand, Lars. . FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications. In Physiological reviews, 99, 1433-1466. doi:10.1152/physrev.00029.2018. https://pubmed.ncbi.nlm.nih.gov/31066629/

6. Bystrom, Rebecca, Levis, Mark J. 2023. An Update on FLT3 in Acute Myeloid Leukemia: Pathophysiology and Therapeutic Landscape. In Current oncology reports, 25, 369-378. doi:10.1007/s11912-023-01389-2. https://pubmed.ncbi.nlm.nih.gov/36808557/

7. Arai, Yasuyuki, Chi, SungGi, Minami, Yosuke, Yanada, Masamitsu. 2022. FLT3-targeted treatment for acute myeloid leukemia. In International journal of hematology, 116, 351-363. doi:10.1007/s12185-022-03374-0. https://pubmed.ncbi.nlm.nih.gov/35532877/

8. Fedorov, Kateryna, Maiti, Abhishek, Konopleva, Marina. 2023. Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions. In Cancers, 15, . doi:10.3390/cancers15082312. https://pubmed.ncbi.nlm.nih.gov/37190240/