Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3 with fms standing for "feline McDonough sarcoma"), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokineFlt3 ligand (FLT3L).
It is expressed on the surface of many hematopoietic progenitor cells. Signalling of FLT3 is important for the normal development of haematopoietic stem cells and progenitor cells.
The FLT3 gene is one of the most frequently mutated genes in acute myeloid leukemia (AML).[5] High levels of wild-type FLT3 have been reported for blast cells of some AML patients without FLT3 mutations. These high levels may be associated with worse prognosis.
FLT3 is composed of five extracellular immunoglobulin-like domains, an extracellular domain, a transmembrane domain, a juxtamembrane domain and a tyrosine-kinase domain consisting of 2 lobes that are connected by a tyrosine-kinase insert. Cytoplasmic FLT3 undergoes glycosylation, which promotes localization of the receptor to the membrane.[6]
CD135 is a class III receptor tyrosine kinase. When this receptor binds to FLT3L a ternary complex is formed in which two FLT3 molecules are bridged by one (homodimeric) FLT3L.[7] The formation of such complex brings the two intracellular domains in close proximity to each other, eliciting initial trans-phosphorylation of each kinase domain. This initial phosphorylation event further activates the intrinsic tyrosine kinase activity, which in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell. Signaling through CD135 plays a role in cell survival, proliferation, and differentiation. CD135 is important for lymphocyte (B cell and T cell) development.
Two cytokines that down modulate FLT3 activity (& block FLT3-induced hematopoietic activity) are:
TGF-beta especially, decreases FLT3 protein levels and reverses the FLT3L-induced decrease in the time that hematopoietic progenitors spend in the G1-phase of the cell cycle.[6]
CD135 is a proto-oncogene, meaning that mutations of this protein can lead to cancer.[9]Mutations of the FLT3 receptor can lead to the development of leukemia, a cancer of bone marrow hematopoietic progenitors. Internal tandem duplications of FLT3 (FLT3-ITD) are the most common mutations associated with acute myelogenous leukemia (AML) and are a prognostic indicator associated with adverse disease outcome.
Gilteritinib, a dual FLT3-AXL tyrosine kinase inhibitor[10] has completed a phase 3 trial of relapsed/refractory acute myeloid leukemia in patients with FLT3 ITD or TKD mutations.[11] In 2017, gilteritinib gained FDA orphan drug status for AML.[12] In November 2018, the FDA approved gilteritinib (Xospata) for treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test.[13]
In July 2023, quizartinib (Vanflyta) was also approved for the treatment of newly diagnosed AML with FLT3 internal tandem duplication (ITD)-positive, as detected by an FDA-approved test.[14] Precisely, it should be used with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy.[14]
Midostaurin was approved by the FDA in April 2017 for the treatment of adult patients with newly diagnosed AML who are positive for oncogenic FLT3, in combination with chemotherapy.[15] The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, which is used to detect the FLT3 mutation in patients with AML.
A paper published in Nature in April 2012 studied patients who developed resistance to FLT3 inhibitors, finding specific DNA sites contributing to that resistance and highlighting opportunities for future development of inhibitors that could take into account the resistance-conferring mutations for a more potent treatment.[18]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T (April 2001). "Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies". Blood. 97 (8): 2434–9. doi:10.1182/blood.V97.8.2434. PMID11290608.
^Mooney CJ, Cunningham A, Tsapogas P, Toellner KM, Brown G. Selective Expression of Flt3 within the Mouse Hematopoietic Stem Cell Compartment. Int J Mol Sci. 2017 May 12;18(5):1037. doi: 10.3390/ijms18051037. PMID 28498310; PMCID: PMC5454949.
^Huret J-L. "FLT3 (FMS-like tyrosine kinase 3)". Atlas of Genetics and Cytogenetics in Oncology and Haematology. University Hospital of Poitiers.
Kottaridis PD, Gale RE, Linch DC (2003). "Prognostic implications of the presence of FLT3 mutations in patients with acute myeloid leukemia". Leuk. Lymphoma. 44 (6): 905–13. doi:10.1080/1042819031000067503. PMID12854887. S2CID44447515.
Gilliland DG (2004). "FLT3-activating mutations in acute promyelocytic leukaemia: a rationale for risk-adapted therapy with FLT3 inhibitors". Best Practice & Research. Clinical Haematology. 16 (3): 409–17. doi:10.1016/S1521-6926(03)00063-X. PMID12935959.
Sternberg DW, Licht JD (2005). "Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges". Curr. Opin. Hematol. 12 (1): 7–13. doi:10.1097/01.moh.0000147891.06584.d7. PMID15604885. S2CID1590938.
Marcucci G, Mrózek K, Bloomfield CD (2005). "Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics". Curr. Opin. Hematol. 12 (1): 68–75. doi:10.1097/01.moh.0000149608.29685.d1. PMID15604894. S2CID6183391.
Stubbs MC, Armstrong SA (2007). "FLT3 as a therapeutic target in childhood acute leukemia". Current Drug Targets. 8 (6): 703–14. doi:10.2174/138945007780830782. PMID17584026.
