Disease relevance of FLT3LG

• Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax [1].
• Interleukin 8 and Flt3 ligand as markers of advanced disease in primary gastrointestinal non-Hodgkin's lymphoma [2].
• Development of complicating bacterial infections then increased the serum levels of both G- and GM-CSF, and the Flt3L levels remained high during the infections [3].
• On the strength of the above findings, it can be concluded that the FL-FLT3 signaling system may play a certain, albeit probably not causal role in the development of human leukemias [4].
• Effect of flt3 ligand on in vitro growth and expansion of colony-forming bone marrow cells from patients with aplastic anemia [5].

High impact information on FLT3LG

• Daily treatment of mice with recombinant human Flt3 ligand (huFlt3L) results in a dramatic numerical increase in the number of dendritic cells (DCs) in vivo [6].
• Here we show that large numbers of over 40% pure CD11c(+)CD11b(-)B220(+)Gr-1(+) IPCs can be generated from mouse bone marrow cultures with FLT3-ligand [7].
• This study demonstrates that the development of murine CD11c(+)CD11b(-)B220(+)Gr-1(+) IPCs and CD11c(+)CD11b(+)B220(-) myeloid DCs is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor [7].
• CD34(++)CD45RA(-) early progenitor cells did not have the capacity to produce large amounts of IFN-alpha/beta in response to viral stimulation; however, they can be induced to undergo proliferation and differentiation into IPCs/pre-DC2 in culture with FLT3 ligand [8].
• Culture of highly purified human CD34(+) bone marrow cells in thrombopoietin/Flt-3 ligand/stem cell factor induced HOXB4 3-10-fold, whereas culture in granulocyte/macrophage colony-stimulating factor, only increased HOXB4/luciferase expression 20-50% [9].

Chemical compound and disease context of FLT3LG

• PURPOSE: This study compared the clinical toxicity and hematological effects of i.p. and s.c. administration of fms-like tyrosine kinase-3-ligand (Flt3-L; Amgen, Thousand Oaks, CA), a truncated glycoprotein that increases dendritic cells (DCs) and monocytes [10].

Biological context of FLT3LG

• Human Flt3 ligand (Flt3L) stimulates early hematopoiesis by activating a type III tyrosine kinase receptor on primitive bone marrow stem cells [11].
• Flt3-L prevented apoptosis in AML blasts [1].
• Effects of human FLT3 ligand on myeloid leukemia cell growth: heterogeneity in response and synergy with other hematopoietic growth factors [12].
• Despite widespread expression of the receptor FLT3 among the leukemia cell lines from certain cell lineages, only two growth factor-dependent myeloid leukemia cell lines showed a significant proliferative response to FL [13].
• The effects of human FLT3 ligand on in vitro human megakaryocytopoiesis [14].

Anatomical context of FLT3LG

• Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors [15].
• Flt3 ligand induces proliferation of quiescent human bone marrow CD34+CD38- cells and maintains progenitor cells in vitro [16].
• Little or no effect was seen with FL on more mature CD34+CD38+ cells from either BM or cord blood [16].
• Flt3-L is produced by BM stromal cells and its receptor is expressed in the majority of acute myeloid leukemia (AML) cases [1].
• Recently, it has been shown the in vivo administration of FL results in a significant alteration of hematopoiesis in murine bone marrow (BM), spleen, peripheral blood, liver and lymph nodes [17].

Associations of FLT3LG with chemical compounds

• Flt3 ligand structure and unexpected commonalities of helical bundles and cystine knots [11].
• Our data indicate additional effects in terms of proliferation and expansion of hematopoietic cells in serum-free conditions when FL and polyethylene glycol (PEG) rhMGDF are included in culture and suggest a differential activity of these cytokines on cells from different hematopoietic sources [18].
• B cells were generated from both progenitor populations in response to the combined effects of KL, FL, and IL-7 [19].
• Culture of G(0) CD34(+) cells isolated based on Hoechst 33342/PyroninY staining with Tpo, SCF and FL for 48 hrs, results in significantly elevated Survivin mRNA and protein levels [20].
• Cell-surface trafficking and release of flt3 ligand from T lymphocytes is induced by common cytokine receptor gamma-chain signaling and inhibited by cyclosporin A [21].

Physical interactions of FLT3LG

• Studies were therefore conducted with murine myeloma BM1 cells expressing Flt3L (membrane bound or soluble forms) or GM-CSF and the IL-12 x CD80 combination [22].

Enzymatic interactions of FLT3LG

• Immunoprecipitation and immunoblotting analyses demonstrated that FLT3/ITDs were constitutively phosphorylated in the absence of FL [23].

Regulatory relationships of FLT3LG

• FL added alone induced DC in the same manner as SCF [24].
• Haematopoietic action of flt3 ligand on cord blood-derived CD34-positive cells expressing different levels of flt3 or c-kit tyrosine kinase receptor: comparison with stem cell factor [25].
• Human FLT3 ligand acts on myeloid as well as multipotential progenitors derived from purified CD34+ blood progenitors expressing different levels of c-kit protein [26].
• However, this required the presence of IL-6 and/or granulocyte/colony-stimulating factor and/or nerve growth factor beta in addition to FL, SF, and IL-3 [27].
• Flt3 ligand synergizes with granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor to mobilize hematopoietic progenitor cells into the peripheral blood of mice [28].

Other interactions of FLT3LG

• FL and SCF were equally effective in stimulating colony formation in combination with IL-3 [29].
• These data indicate that multiple cytokines are necessary to optimally stimulate the proliferation of both classes of MK progenitor cells and that FL plays a significant role in this process by amplifying the MK-CSA of GM-CSF, IL-3, and KL [14].
• Although FL alone exhibited a limited potential in sustaining long-term megakaryocytopoiesis in vitro, it synergistically augmented the ability of IL-3 and KL, alone or in association, to promote long-term megakaryocytopoiesis [14].
• HUVEC transfected with adenovectors expressing TPO, KL, and FL provided the best co-culture system for expanding CD34(+) cells [30].
• Our results suggest that higher pretreatment serum levels of IL-8 and Flt3L are associated with higher stage (>or= II) and high grade, respectively [2].

Analytical, diagnostic and therapeutic context of FLT3LG

• Using long term stromal cocultivation assays, we studied the effects of FL on proliferation and differentiation of a highly primitive and cytokine nonresponsive subpopulation of human HPC, CD34+cd38- cells [16].
• The possible applications of FL in dendritic cell-based immunotherapies are discussed [17].
• Dissection of the exact molecular pathways that lead to proliferation and/or anti-apoptosis of myeloid leukemia cells as well as the detailed elucidation of the possible contribution of the FL-FLT3 genes to leukemogenesis remain future challenges [4].
• Given the functional properties of FL, its synergistic mobilization with G-CSF, and its anticipated good tolerance (because of the absence of an effect on mast cell activation), a clinical use is projected for this cytokine in peripheral blood transplantation settings, as well as in experiments with ex vivo gene transfer [31].
• Soluble Flt3-L was undetectable (< 100 pg/mL) by ELISA assay of conditioned medium from transduced cells, but Flt3-L was detected on the surface of AML5 cells by FACS analysis [32].

References