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FLT3 Gene Editing 
FLT3 encodes a receptor tyrosine kinase (RTK) expressed on normal hematopoietic stem/progenitor cells. FLT3 dimerizes and autophosphorylates upon binding of FLT3 ligand (FLT3L), activating the intracellular tyrosine kinase domain, which results in phosphorylation of downstream molecules, thereby activating signaling cascades that promote transcription of genes regulating survival, proliferation, and differentiation. FLT3 is silenced in the process of hematopoietic differentiation.
FLT3 Mutations
Acute myelogenous leukemia (AML) is a clonal disorder of hematopoietic stem cells which is caused by acquired and occasionally inherited genetic alterations. In 1996, an internal tandem duplication mutation in the JM domain-coding sequence of the FLT3 gene (FLT3-ITD) was first identified in AML cells. Subsequently, a missense point mutation at the D835 residue and point mutations, insertions and deletions in the codons surrounding D835 within a tyrosine kinase domain of FLT3 (FLT3-KDM) were identified. ITD and tyrosine kinase domain (TKD) mutations are activating, causing ligand-independent, or constitutive, FLT3 receptor signaling, and thus promote cytokine-independent AML cell survival and proliferation. FLT3 mutations are identified in approximately 30% of the adult patients with AML, and are highly associated with leukocytosis and poor prognosis.
Targeting FLT3 to Treat Leukemia
ITD of the FLT3 receptor gene invariably results in the constitutive activation of the RTK and its downstream signaling effectors, such as STAT5, RAS/RAF/MEK/ERK kinases, and PI3-kinase. Therefore, altered mechanisms of cellular proliferation and apoptosis promote cell survival thereby conferring a substantial growth advantage to leukemic stem and progenitor cells. From a clinical perspective, this usually translates into a higher percentage of blood and bone marrow blasts, and a worse overall survival primarily owing to a high relapse rate. Lines of evidence show that the allelic burden plays a key role in predicting the level of ‘FLT3 addiction’ and clinical outcome.
As FLT3 mutations cause ligand-independent cell survival, proliferation, and resistance to apoptosis, it was speculated that inhibiting FLT3 signaling would produce cytotoxicity and clinical responses. The primary approach has been identifying and testing of small-molecule inhibitors of FLT3 signaling, but some work has also focused on developing internalizing fully human antagonistic antibodies directed against FLT3. Many FLT3 inhibitors have been studied. Besides a variety of improved treatment strategies in AML, the recognition that FLT3-ITD is an adverse prognostic marker, the integration of FLT3 inhibitors into the treatment algorithm, and the increased use of allogeneic hematopoietic stem cell transplant (alloHSCT) have led to improvements in clinical outcomes in patients with FLT3-ITD-mutated AML over the past 15 years. Generally, the use of FLT3 inhibitors, compared with historical outcomes before their emergence, has shown a substantial clinical benefit in the relapsed/refractory AML setting and offers promising treatment strategies for patients with few options. For example, quizartinib, an oral, selective, and highly potent next-generation FLT3 inhibitor, significantly improved overall survival (OS) in a retrospective analysis in patients with FLT3-ITD-mutated AML who had relapsed after alloHSCT or after the failure of second-line salvage chemotherapy compared with similar patients not treated with FLT3 inhibitors.
FLT3 Gene Editing Service
CRISPR/Cas9 PlatformCB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control FLT3 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.
| Service | Details | Alternative cell lines or animal species |
| FLT3 Gene Editing Cell Line Generation | gRNA design and synthesis Transfect the cell lines you’re interested Select the high expression cells and sort monoclonal cell Validate the knockout/knockin/point mutation of FLT3 by PCR and sequencing Provide cryogenic preserved vials of stable cells and final reports | HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc. |
| FLT3 Gene Editing Animal Model Generation | FLT3 gene conventional knockout animals FLT3 gene conditional knockout animals FLT3 point mutation animals FLT3 knockin animals | Mouse, rat, rabbit, zebrafish, C. elegans, etc. |
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References
- Hassanein M, et al. FLT3 inhibitors for treating acute myeloid leukemia. Clinical Lymphoma Myeloma and Leukemia, 2016, 16(10): 543-549.
- Larrosa-Garcia M, Baer M R. FLT3 inhibitors in acute myeloid leukemia: current status and future directions. Molecular cancer therapeutics, 2017, 16(6): 991-1001.
- Konig H, Levis M. Targeting FLT3 to treat leukemia. Expert opinion on therapeutic targets, 2015, 19(1): 37-54.
- Kiyoi H. Flt3 inhibitors: recent advances and problems for clinical application. Nagoya journal of medical science, 2015, 77(1-2): 7.
- Daver N, et al. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia, 2019, 33(2): 299-312.