Disease relevance of Flt3l

• We sought to determine if DCs generated by using Flt3L then matured with lipopolysaccharide (LPS) could lead to DCs with in vivo anti-acute myelogenous leukemia (anti-AML) activity [1].
• Using human papillomavirus-16 E7 as a model antigen, we evaluated the effect of linkage to FL on the potency of antigen-specific immunity generated by naked DNA vaccines administered intradermally via gene gun [2].
• The combination of the Flt3 ligand and the vaccine also decreased the incidence of metastases and was the most effective treatment [3].
• SF-MDR provirus integration assessed by quantitative real-time polymerase chain reaction (PCR) was optimal in the presence of Flt-3 ligand/thrombopoietin/stem-cell factor, resulting in a 6-fold (24% +/- 5% [mean +/- SE]) higher average proportion of gene-marked human cells in NOD/SCID mice than that achieved with IL-3 alone (P <.01) [4].
• Flt3 ligand antitumor activity in a murine breast cancer model: a comparison with granulocyte-macrophage colony-stimulating factor and a potential mechanism of action [5].

Psychiatry related information on Flt3l

• However, the most powerful antimyeloma effects were induced by Flt3-L + Id vaccination + IL-2: 81% of the treated animals experienced long-term survival (> 180 d) [6].

High impact information on Flt3l

• Since DCs are pivotal in the induction of immune responses, we tested whether Flt3L treatment of mice challenged with a syngeneic methylcholanthrene (MCA)-induced fibrosarcoma would augment the generation of effective antitumor immune responses in vivo [7].
• This pathway is represented within Flt-3 Ligand-derived dendritic cells (DCs) that represent immature lymphoid DCs, but not within GM-CSF-treated bone marrow-derived dendritic cells [8].
• STAT3 is required for Flt3L-dependent dendritic cell differentiation [9].
• In this report we present the first evidence for a nonredundant regulator of this process, in that adult mice deficient in expression of the flt3 ligand (FL) have severely (10-fold) reduced levels of the CLP, accompanied by reductions in the earliest identifiable B and T cell progenitors [10].
• Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool [10].

Chemical compound and disease context of Flt3l

• Evaluation of dysregulation of the receptor tyrosine kinases Kit, Flt3, and Met in histiocytic sarcomas of dogs [11].
• Similarly, B4B8FL and B4B8 cells were transfected with herpes simplex virus thymidine kinase (HSVTK) to produce B4B8TK and B4B8FL/TK cells, which should be sensitive to ganciclovir (GCV), to know whether the effects of Flt3-L and HSVTK/GCV would be synergistic [12].

Biological context of Flt3l

• FLT3 ligand preserves the ability of human CD34+ progenitors to sustain long-term hematopoiesis in immune-deficient mice after ex vivo retroviral-mediated transduction [13].
• Cell-cycle analysis showed that shortening of cell-cycle time induced by FL is mainly because of alteration in the G1 phase that hematopoietic progenitors go through [14].
• The chromosomal location of the FL gene has been mapped, by in situ hybridization, to chromosome 7 in mouse and chromosome 19 in human [15].
• The present study is the first demonstrating cytokines capable of inhibiting FL-stimulated hematopoietic cell growth [16].
• The message for FL is unusually ubiquitous, whereas that of its receptor is quite restricted, apparently limiting the function of the ligand to fetal development and early hematopoiesis [15].

Anatomical context of Flt3l

• The FLT3 ligand potently and directly stimulates the growth and expansion of primitive murine bone marrow progenitor cells in vitro: synergistic interactions with interleukin (IL) 11, IL-12, and other hematopoietic growth factors [17].
• Thus, FL emerges as a potent synergistic HGF, that in combination with numerous other HGFs, can directly stimulate the proliferation, myeloid differentiation, and expansion of primitive hematopoietic progenitor cells [17].
• Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells [18].
• A neutralizing anti-TGF-beta antibody showed the presence of endogenous TGF-beta in the cultures and potently enhanced the ability of FL to stimulate progenitor cell growth in the absence of other cytokines [16].
• Finally, even though most cell lines express some amount of FL mRNA, we found that very little FL protein is actually made, with T cells and stromal cells being the major producers [15].

Associations of Flt3l with chemical compounds

• Natural FL protein has been purified from a stromal cell line and shown to be a 65 kD nondisulfide-linked homodimeric glycoprotein comprised of 30 kD subunits, each containing 12 kD of N- and O-linked sugars [15].
• The inhibitor LY294002 was able to completely abolish survival mediated by KL, whereas IL-3 and FL were only partially affected [19].
• In contrast, culture with IL-7 + IGF-1 or Flt3-L had minimal effects on E2A protein levels [20].
• Flt3 ligand elicits a variety of effects on early hemopoietic progenitors by occupying its cognate receptor, Flt3, a member of the type III tyrosine kinase receptor family [21].
• GM-CSF/IL-4/LPS was superior to Flt3L/LPS for generating anti-AML effects in vivo [1].

Physical interactions of Flt3l

• FL interacted with SCF or with IL-7 to stimulate their growth resulting in a 20- and 50-fold increase in cellularity, respectively [22].

Regulatory relationships of Flt3l

• Results from our serial observations of colony formation and replating experiments suggest that FL enhances the rate of growth of interleukin-3 (IL-3)-dependent colonies by shortening the time for each progenitor in the colonies to divide [14].
• Ability of flt3 ligand to stimulate the in vitro growth of primitive murine hematopoietic progenitors is potently and directly inhibited by transforming growth factor-beta and tumor necrosis factor-alpha [16].
• Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo [23].
• OBJECTIVE: We have previously shown that Flt3 ligand (FL)/Flt3 signaling regulates hematopoietic cell migration by modulating the SDF1alpha/CXCR4 signaling pathway [24].
• Intrarenal CCL5 production was enhanced by Flt3L administration, in association with marked increases in interstitial CD45+ mononuclear cells [25].

Other interactions of Flt3l

• It was found that the soluble receptor induced a substantial decrease in osteoclast number, strongly suggesting that FL is responsible for the partial compensation for M-CSF deficiency that occurs in these mice [26].
• TGF-beta 1 inhibited more than 96% of the myeloid colony formation in response to these cytokine combinations, whereas TNF-alpha reduced the number of colonies by 58% to 96% depending on the cytokine by which FL was combined [16].
• E2A expression in vitro was also assessed in cultures supplemented with IL-7 +/- recombinant murine SCF (rmSCF), insulin-like growth factor-1 (rhIGF-1), or Flt3-ligand (rhFlt3-L) [20].
• Accumulation of HPC in spleen is accompanied by increased mRNA for flt3-ligand and OSM [27].
• Accordingly, FL in combination with G-CSF or IL-11 expanded the number of progenitors more than 40-fold after 2 wk incubation [17].

Analytical, diagnostic and therapeutic context of Flt3l

• FL treatment of recipients before allogeneic bone marrow transplantation dramatically suppressed donor T-cell responses to host antigens, thereby reducing GVHD mortality (P <.01) [28].
• Northern blot analysis shows widespread expression of flt3 ligand mRNA transcripts in human tissues [29].
• Heart, but not skin, allografts from donors lacking Flt3 ligand exhibit markedly prolonged survival time [30].
• Adoptive transfer of Ag-pulsed mFlt3L splenic DC to naive mice actually caused faster rates of tumor growth and induced minimal CTL compared with control DC. mFlt3L also failed to protect against tumors in which human Flt3 ligand was protective, but depletion of CD4(+) T cells restored tumor protection [31].
• Treatment with Flt3-L of presensitized mice significantly suppressed (p < 0.001) the late allergic response, AHR, bronchoalveolar lavage fluid total cellularity, absolute eosinophil counts, and inflammation in the lung tissue [32].

References