The FLT3 receptor
FMS-like tyrosine 3 (FLT3) is a member of the class III receptor tysosine kinase family, structurally related to the KIT, FMS and PDGF receptors. FLT3 is expressed in most acute leukemias, including 94% of B-lineage acute lymphoblastic leukemia (ALL), 34% of T-lineage ALL, and 89% of acute myelogenous leukemia (AML) cases. This class of receptor is characterized by five extracellular immunoglobulin-like domain that bind ligand, a single transmembrane domain, a juxtamembrane region, and an intracellular kinase domain interrupted by a kinase insert. Ligand binding promotes receptor dimerization and activation of the kinase domain resulting in auto-transphosphorylation of specific tyrosines.
Activated FLT3 can then phosphorylate target proteins and also serves as a docking site for a variety of proteins with SH2 domains involved in intracellular signaling cascades. Activated FLT3 mediates signaling through at least three downstream signaling pathways: , and mitogen-activated protein (MAP) kinase. These signaling pathway are involved in cell differentiation, proliferation and survival. The FLT3 receptor is normally involved in differentiation, proliferation and survival of multipotent hematopoietic stem cells, and lymphoid and dendritic progenitor cells. Abnormal expression/activation of FLT3 appears to play various roles in the development of leukemia, particularly AML and infant ALL.
FLT3 is often activated by mutations including internal tandem duplications (ITD) in the juxtamembrane domain or point mutations in the kinase domain. AML patients with FLT3-ITD mutations have a poor prognosis. In addition, overexpression of wild-type FLT3 with FLT3 ligand (FL) also leads to constitutive activation of the FLT3 kinase domain. Fms-like tyrosine kinase 3 ligand (Flt3L) is a potent co-stimulatory cytokine that plays a role in proliferation, differentiation and survival of hematopoietic stem and progenitor cells (Lyman and McKenna, 2003). In the mouse, Flt3L is an 18kDa protein comprised of 162 amino acids and is ancestrally related to colonystimulating factor-1 (CSF-1) ligand and c-kit ligand. Human Flt3L is similar in structure and function to the mouse cytokine.
FLT3 tyrosine kinase inhibitors and limitations
Taken together, these observations suggest FLT3 may be a viable candidate for molecularly targeted therapy. In fact, various anti-FLT3 tyrosine kinase inhibitors (TKI) have been developed and some of the best-studied FLT3 inhibitors to date include: , MLN518, SU11248 and AG1295. Although these inhibitors vary in their degree of FLT3 inhibition and selectivity for FLT3, all are able to induce cytotoxicity in FLT3 expressing cells in vitro and/or in vivo. Furthermore, clinical trials with some of these inhibitors demonstrate their ability to decrease peripheral blood and bone marrow blast counts in some patients. Due to promising clinical trial results, CEP-701 is currently being tested on AML in a randomized Phase Ⅱ clinical trial in combination with chemotherapy and as a single agent in pediatric ALL.
Although FLT3 inhibitors demonstrate some preclinical and clinical efficacy, they possess a number of limitations. Clinical trials revealed that FLT3 TKIs are able to sufficiently reduce the number of blasts leading to measurable clinical responses in a minority of patients and that this effect is transitory. This may be due to insufficient FLT3 inhibition, a lack of dependence on FLT3 signaling for cellular proliferation and survival and/or selection of resistant cell populations. Futhermore, most cases of AML and ALL do not involve mutant FLT3 and it is unclear to what degree these cells depend on FLT3 signaling for sustaining the leukemic phenotype. At drug concentrations necessary to inhibit FLT3 phosphorylation past a critical threshold required to induce cytotoxicity, a spectrum of other kinases are sometimes also inhibited which can lead to toxicities. Even when cells are dependent on FLT3 signaling for survival and proliferation, prolonged exposure to TKIs can select for resistant clones, as has been seen with Gleevac, a TKI targeting BCR-ABL in chronic myelogenous leukemia (CML).
Anti-FLT3 immunotherapy is an alternative to TKIs. Antibodies are very specific and therefore less toxic than TKIs and have the added advantage of recruiting the host’s immune system (i.e. antibody dependant cell-mediated cytotoxicity) in clearing leukemic cells. In this dissertation Ⅰ explore the therapeutic potential of anti-FLT3 immunotherapy for the treatment of acute leukemias.
Piloto, O. (2006). Anti-FLT3 immunotherapy for the treatment of acute leukemias.
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