Rabbit Anti-Human FLT3 monoclonal antibody, clone S.368.7

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The most clinically important point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in acute myeloid leukemia (AML) patients. There are two major types of FLT3 mutations: internal tandem duplication mutations in the juxtamembrane domain (FLT3-ITD) and point mutations or deletion in the tyrosine kinase domain (FLT3-TKD). Both mutant FLT3 molecules are activated through ligand-independent dimerization and trans-phosphorylation. Mutant FLT3 induces the activation of multiple intracellular signaling pathways, mainly STAT5, MAPK and AKT signals, leading to cell proliferation and anti-apoptosis. Because high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot sufficiently improve the prognosis, clinical development of FLT3 kinase inhibitors expected. Although several FLT3 inhibitors have been developed, it takes more than 20 years from the first identification of FLT3 mutations until FLT3 inhibitors become clinically available for AML patients with FLT3 mutations. To date, three FLT3 inhibitors have been clinically approved as monotherapy or combination therapy with conventional chemotherapeutic agents in Japan and/or Europe and United states. However, several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous. Further basic and clinical studies are required to establish the best therapeutic strategy for AML patients with FLT3 mutations.

Neutrophils act as both messenger and effector which contributed to the pathogenesis of acute lung injury (ALI). Targeting neutrophils could be a novel strategy for prevention and treatment of ALI. Selaginella uncinata is widely used as an antitussive, antipyretic and anti-inflammatory herb to treat various pulmonary diseases, including lung cancer, asthma, pulmonary fibrosis and pneumonia. However, its effective constituents remain unknown. In the present study, the protective effects of flavonoids from S. uncinata (SUF) and its major compound robustaflavone-4'-dimethyl ether (RDE) against lipopolysaccharide (LPS)-induced ALI were investigated in mice and in neutrophils. The results showed that both SUF and RDE had the same inhibition on LPS-induced lung edema and neutrophil infiltration as well as the increased levels of IL-6, TNF-alpha, P-selectin and ICAM-1 in serum of LPS-challenged mice. Furthermore, RDE significantly inhibited inducible neutrophil activation in a concentration-dependent manner, and also reduced the levels of intracellular calcium as well as the expressions of CCR2. Rescue experiment showed that RDE suppressed FLT3 and its downstream p-p38 and p-AKT, which could be abolished by FLT3 agonist FLT3L but partly by MAPK agonist PDBu or AKT agonist SC79. Therefore, these results indicated that RDE as the main bioactive compound in SUF alleviated LPS-induced acute lung injury and inhibited neutrophil activation via inhibition of FLT3-mediatied AKT and MAPK pathways.