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J.m. Bertho - One of the best experts on this subject based on the ideXlab platform.

  • Use of Flt3 Ligand to Evaluate Residual Hematopoiesis after Heterogeneous Irradiation in Mice
    Radiation research, 2006
    Co-Authors: Marie Prat, C. Demarquay, J. Frick, D. Thierry, N. Dudoignon, J.m. Bertho
    Abstract:

    Abstract Prat, M., Demarquay, C., Frick, J., Dudoignon, N., Thierry, D. and Bertho, J. M. Use of Flt3 Ligand to Evaluate Residual Hematopoiesis after Heterogeneous Irradiation in Mice. Radiat. Res. 166, 504–511 (2006). We evaluated the possibility of using plasma Flt3 Ligand (FL) concentration as a biological indicator of bone marrow function after heterogeneous irradiation. Mice were irradiated with 4, 7.5 or 11 Gy with 25, 50, 75 or 100% of the bone marrow in the field of irradiation. This model of irradiation resulted in graded and controlled damage to the bone marrow. Mice exhibited a pancytopenia correlated with both the radiation dose and the percentage of bone marrow irradiated. The FL concentration in the blood increased with the severity of bone marrow aplasia. Nonlinear regression analysis showed that the FL concentration was strongly correlated with the total number of residual colony-forming cells 3 days after irradiation, allowing a precise estimate of residual hematopoiesis. Moreover, the FL...

  • Kinetics of plasma Flt3 Ligand concentration in hematopoietic stem cell transplanted patients
    Leukemia & lymphoma, 2006
    Co-Authors: Marie Prat, J. Frick, D. Thierry, N.-c. Gorin, Jean-philippe Laporte, J.m. Bertho
    Abstract:

    The present study aimed to follow-up variations in plasma Flt3 Ligand (FL) concentration after hematopoietic stem cell transplantation and to compare the influence of conditioning regimens on variations in FL concentration. Ten patients undergoing a conditioning regimen, including BEAM, cyclophosphamide (Cy) + total body irradiation or Cy + anti-thymocyte globulins (ATG), which was then followed by hematopoietic stem cell transplantation, were studied. Plasma FL concentrations, white blood cell (WBC) expression of both FL mRNA and the membrane-bound form of FL were carried out at different times post-treatment. The results indicated that plasma FL concentration increased rapidly after the conditioning regimen in all patients, in correlation with the decrease in number of WBCs. The area under the curve of FL according to time was directly correlated with the duration of pancytopenia, except when ATG was included in the conditioning regimen. Although the number of patients was limited in this study, the comparison of ATG-treated patients and other patients suggests that plasma FL concentration is regulated by a complex mechanism partly involving circulating blood cells.

  • Radiation-induced increase in plasma Flt3 Ligand concentration in mice: Evidence for the implication of several cell types
    Radiation Research, 2005
    Co-Authors: Marc Prat, C. Demarquay, J. Frick, D. Thierry, N.-c. Gorin, J.m. Bertho
    Abstract:

    Circulating T lymphocytes were proposed as the main producer of Flt3 Ligand. However, during aplasia, there is a drastic reduction in the number of T lymphocytes, while plasma Flt3 Ligand concentration is increased. This contradiction prompted us to compare variations in plasma Flt3 Ligand during radiation-induced aplasia in BALB/c mice and in T-lymphocyte-deficient NOD-SCID mice to delineate the role of T lymphocytes in the increase in Flt3 Ligand concentration. The results showed that plasma Flt3 Ligand concentration was increased similarly in the two strains of mice, and that Flt3 Ligand concentration was negatively correlated to the number of residual hematopoietic progenitors. Moreover, the Flt3 Ligand mRNA expression and Flt3 Ligand protein concentration were similar in the two strains of mice in all organs tested, i.e. thymus, spleen, bone marrow, liver, brain and blood cells. These results confirm that Flt3 Ligand concentration in the blood is a reflection of bone marrow function and that T lymphocytes are not the main regulator of Flt3 Ligand variations during aplasia. © 2005 by Radiation Research Society.

  • Radiation-induced increase in plasma Flt3 Ligand concentration in mice: evidence for the implication of several cell types.
    Radiation research, 2005
    Co-Authors: Marie Prat, C. Demarquay, J. Frick, D. Thierry, N.-c. Gorin, J.m. Bertho
    Abstract:

    Abstract Prat, M., Demarquay, C., Frick, J., Thierry, D., Gorin, N. C. and Bertho, J. M. Radiation-Induced Increase in Plasma Flt3 Ligand Concentration in Mice: Evidence for the Implication of Several Cell Types. Radiat. Res. 163, 408–417 (2005). Circulating T lymphocytes were proposed as the main producer of Flt3 Ligand. However, during aplasia, there is a drastic reduction in the number of T lymphocytes, while plasma Flt3 Ligand concentration is increased. This contradiction prompted us to compare variations in plasma Flt3 Ligand during radiation-induced aplasia in BALB/c mice and in T-lymphocyte-deficient NOD-SCID mice to delineate the role of T lymphocytes in the increase in Flt3 Ligand concentration. The results showed that plasma Flt3 Ligand concentration was increased similarly in the two strains of mice, and that Flt3 Ligand concentration was negatively correlated to the number of residual hematopoietic progenitors. Moreover, the Flt3 Ligand mRNA expression and Flt3 Ligand protein concentration we...

  • Le Flt3-Ligand plasmatique, un bio-indicateur pronostique de l'atteinte radio-induite à la moelle osseuse
    Radioprotection, 2001
    Co-Authors: J.m. Bertho, C. Demarquay, J. Frick, N.-c. Gorin, J. Ph. Laporte, Jocelyne Aigueperse, Patrick Gourmelon
    Abstract:

    Plasma Flt3-Ligand as a prognostic bio-indicator of radiation-induced bone marrow damage. Following an accidental irradiation, the choice between different therapeutic strategies mainly depends upon the estimated radiation-induced bone marrow damage. It was shown recently that the serum concentration of Flt3-Ligand (FL), a cytokine mainly acting on immature haemopoietic cells, is highly elevated in either acquired or induced bone marrow aplasia. This suggested to us that FL measurement could be used as a bio-indicator of radiation-induced bone marrow damage. In order to verify this hypothesis, studies were conducted in a non human primate model as well as in humans undergoing radio and/or chemotherapy. Results showed that the increase in FL concentration on day 5 after irradiation is predictive of the evolution of the haemopoietic syndrome. Similar results were obtained in humans. Overall these results suggested that FL measurement could be used as a reliable bio-indicator of radiation-induced bone marrow damage in accidental irradiation situations.

Ugur Sahin - One of the best experts on this subject based on the ideXlab platform.

  • Flt3 Ligand as a Molecular Adjuvant for Naked RNA Vaccines.
    Methods in molecular biology (Clifton N.J.), 2016
    Co-Authors: Sebastian Kreiter, Mustafa Diken, Abderraouf Selmi, Özlem Türeci, Jutta Petschenka, Ugur Sahin
    Abstract:

    Intranodal immunization with antigen-encoding naked mRNA has proven to be an efficacious and safe approach to induce antitumor immunity. Thanks to its unique characteristics, mRNA can act not only as a source for antigen but also as an adjuvant for activation of the immune system. The search for additional adjuvants that can be combined with mRNA to further improve the potency of the immunization revealed Fms-like tyrosine kinase 3 (Flt3) Ligand as a potent candidate. Systemic administration of the dendritic cell-activating Flt3 Ligand prior to or along with mRNA immunization-enhanced priming and expansion of antigen-specific CD8(+) T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodally administered mRNA. Both compounds demonstrate a successful combination in terms of boosting the immune response. This chapter describes methods for intranodal immunization with naked mRNA by co-administration of Flt3 Ligand, which leads to strong synergistic effects.

  • Flt3 Ligand Enhances the Cancer Therapeutic Potency of Naked RNA Vaccines
    Cancer research, 2011
    Co-Authors: Sebastian Kreiter, Mustafa Diken, Abderraouf Selmi, Jan Diekmann, Sebastian Attig, Yves Hüsemann, Michael Koslowski, Christoph Huber, Özlem Türeci, Ugur Sahin
    Abstract:

    Intranodal immunization with antigen-encoding naked RNA may offer a simple and safe approach to induce antitumor immunity. RNA taken up by nodal dendritic cells (DC) coactivates toll-like receptor (TLR) signaling that will prime and expand antigen-specific T cells. In this study, we show that RNA vaccination can be optimized by coadministration of the DC-activating Fms-like tyrosine kinase 3 (Flt3) Ligand as an effective adjuvant. Systemic administration of Flt3 Ligand prior to immunization enhanced priming and expansion of antigen-specific CD8 + T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodal RNA. Unexpectedly, plasmacytoid DCs (pDC) were found to be essential for the adjuvant effect of Flt3 Ligand and they were systemically expanded together with conventional DCs after treatment. In response to Flt3 Ligand, pDCs maintained an immature phenotype, internalized RNA, and presented the RNA-encoded antigen for efficient induction of antigen-specific CD8 + T-cell responses. Coadministration of Flt3 Ligand with RNA vaccination achieved remarkable cure rates and survival of mice with advanced melanoma. Our findings show how to improve the simple and safe strategy offered by RNA vaccines for cancer immunotherapy. Cancer Res; 71(19); 6132–42. ©2011 AACR .

Dania Caron - One of the best experts on this subject based on the ideXlab platform.

  • Flt3-Ligand as a Vaccine Adjuvant: Results in a Study of Flt3-Ligand Plus Tetanus Toxoid Immunization
    2004
    Co-Authors: Stephen Chui, Timothy M. Clay, Paul J. Mosca, Amy Hobeika, Takuya Osada, Laurent J. Galibert, Dania Caron, H. Kim Lyerly, Michael A. Morse
    Abstract:

    Dendritic cells (DC) efficiently process and present antigens to the effector arm of the immune system,thereby stimulat- ing immunity against antigens of both foreign and self origin.Administration of Flt3-Ligand (FL) has been reported to increase dendritic cell (DC) numbers in

  • Pilot study of an HLA-A2 peptide vaccine using Flt3 Ligand as a systemic vaccine adjuvant.
    Journal of clinical immunology, 2003
    Co-Authors: Douglas G. Mcneel, Dania Caron, Keith L. Knutson, Kathy Schiffman, Donna Davis, Mary L. Disis
    Abstract:

    A pilot vaccine study was conducted to test the safety and immunological efficacy of four monthly immunizations of an MHC class I peptide vaccine, the E75 HLA-A2 epitope from HER-2/neu, using Flt3 Ligand as a systemic vaccine adjuvant. Twenty HLA-A2-expressing subjects with advanced stage prostate cancer were randomly assigned to one of four immunization or treatment schedules: (a) Flt3 Ligand (20 μ g/kg per day) administered subcutaneously daily for 14 days on a 28-day cycle, monthly for four months; (b) Flt3 Ligand course as above with the E75 peptide vaccine administered on day 7 of each Flt3 Ligand cycle; (c) Flt3 Ligand course as above with the E75 peptide vaccine administered on day 14 of each Flt3 Ligand cycle; or (d) E75 peptide admixed with granulocyte–macrophage colony-stimulating factor and administered intradermally once every 28 days, as has previously been reported. The primary endpoints of the study were the determination of safety and immunological efficacy in generating E75-specific T cells as determined by peptide-specific interferon-gamma ELIspot. Adverse events included one grade 3 skin reaction and the development of grade 2 autoimmune hypothyroidism in two subjects with preexisting subclinical autoimmune hypothyroidism. Dendritic cells were markedly increased in the peripheral blood of subjects receiving Flt3 Ligand with each repetitive cycle, but augmentation of antigen-presenting cells within the dermis was not observed. Apart from a single subject, no significant peptide-specific T-cell responses were detected by ELIspot, whereas delayed-type hypersensitivity responses were detectable in control subjects and in subjects receiving peptide vaccine early in the course of Flt3 Ligand administration. The absence of robust peripheral immune responses in the current study may be attributable to the small numbers of subjects or differences in the subject population. In addition, the inability of Flt3 Ligand to augment the number of peripheral skin antigen-presenting cells may have contributed to the absence of robust peptide-specific immunity detectable in the peripheral blood of immunized subjects treated with Flt3 Ligand.

  • The use of Flt3 Ligand as an adjuvant for hepatitis B vaccination of healthy adults.
    Vaccine, 2002
    Co-Authors: Thomas G Evans, Muhammad Hasan, Laurent Galibert, Dania Caron
    Abstract:

    A phase I/II clinical trial was carried out to determine the safety of Flt3 Ligand used as a vaccine adjuvant when administered to healthy human volunteers on two different schedules. In the first phase of this study, Flt3 Ligand was administered SQ at a dose of 20 microg/kg (to a maximum of 1500 microg) every day (N=10) or every other day (N=10) for 1 week. The Flt3 Ligand injection series was followed 1 day later by the first of three vaccinations with the licensed hepatitis B vaccine. In the second phase of the trial, 30 volunteers received either Flt3 Ligand or placebo on the alternate day schedule in a randomized, double-blind design. The Flt3 Ligand injections were safe and very well-tolerated. The number of lineage negative, HLA-DR(hi), CD11c(+), CD123(-) dendritic cells (DCs) increased 23-fold, and the lineage negative, HLA-DR(hi), CD11c(-), CD(123 bright) pre-DCs increased 6-fold. There was an associated increase in monocytes and WBCs in the Flt3 Ligand recipients. Despite the marked increase in peripheral circulating dendritic cells, no increase was observed in the hepatitis B antibody titers induced after vaccination.

  • Mobilization of Dendritic Cell Precursors in Patients With Cancer by Flt3 Ligand Allows the Generation of Higher Yields of Cultured Dendritic Cells
    Journal of immunotherapy (Hagerstown Md. : 1997), 2002
    Co-Authors: Carlos E. Marroquin, Dania Caron, Jennifer A. Westwood, Réjean Lapointe, Arnold Mixon, John R. Wunderlich, Steven A. Rosenberg, Patrick Hwu
    Abstract:

    Flt3 Ligand (Flt3L) stimulates the proliferation and differentiation of hematopoietic cells. Subcutaneous Flt3L administration has been shown to effectively manage some murine cancers and in humans, to lead to an increase in peripheral blood monocyte and dendritic cell (DC) counts. In the current study, we determined the effects of Flt3L therapy on patients with melanoma and renal cancer, and in particular, if Flt3L could be used either by enhancing the immunization of patients with melanoma to tumor antigen peptides in vivo, or by mobilizing DC precursors to allow the production of larger numbers of cultured DC. Flt3 Ligand administration resulted in a 19-fold increase in DC counts in the peripheral blood of patients. The DC generated in vivo appeared only partially activated, expressing increased levels of CD86, CD33, and major histocompatibility complex class II, but no or low levels of CD80 and CD83. This partial activation may account for the lack of enhanced immune responses to melanoma antigens and absence of clinical responses in the patients even in combination with antigen immunization. Flt3 Ligand administration did result, however, in a 7-fold increased yield of monocytes per liter of blood from leukapheresed patients. Dendritic cells were as readily generated from monocytes collected before and after Flt3L therapy, and they stimulated allogeneic T-cell proliferation in a mixed leukocyte reaction to a similar magnitude. Thus, the use of Flt3L may be an important method to mobilize DC precursors to allow patient therapy with larger numbers of cultured DC.

  • In vivo generation of human dendritic cell subsets by Flt3 Ligand
    Blood, 2000
    Co-Authors: Eugene Maraskovsky, Dania Caron, Elizabeth Daro, Eileen R. Roux, Mark Teepe, Charlie Maliszewski, Jeannie Hoek, Mel E. Lebsack, Hilary J. Mckenna
    Abstract:

    Dendritic cells (DCs) represent a family of ontogenically distinct leukocytes involved in immune response regulation. The ability of DCs to stimulate T-cell immunity has led to their use as vectors for immunotherapy vaccines. However, it is unclear whether and to what degree in vitro-generated DCs are representative of DCs that develop in vivo. Treatment of mice with human Flt3 Ligand (FL) dramatically increases the number of DCs. We report here that administration of FL to healthy human volunteers increased the number of circulating CD11c(+ )IL-3Ralpha(low) DC (mean 44-fold) and CD11c(-) IL-3Ralpha(high) DC precursors (mean 12-fold). Moreover, the CD11c(+ )DCs were efficient stimulators of T cells in vitro. Thus, FL can expand the number of circulating, functionally competent human DCs in vivo.

Hilary J. Mckenna - One of the best experts on this subject based on the ideXlab platform.

  • COMPARISON OF THE FUNCTIONAL PROPERTIES OF MURINE DENDRITIC CELLS GENERATED IN VIVO WITH Flt3 Ligand, GM-CSF AND Flt3 Ligand PLUS GM-CSF
    Cytokine, 2002
    Co-Authors: Elizabeth Daro, Mark Teepe, Charles Maliszewski, Eric A. Butz, Jeffrey S. Smith, Hilary J. Mckenna
    Abstract:

    Flt3 Ligand (FL) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are important growth factors for dendritic cells (DC). Substantial numbers of DC can be generated in vivo following the administration of either factor. We sought to extend our knowledge of the functional properties of these cells including their ability to prime naive CD8(+) T cells. In addition, we compared the nature of the DC generated in vivo with the single cytokines to those generated with the combination of FL+polyethylene glycol-modified GM-CSF (pGM-CSF). Treatment with FL+pGM-CSF yielded greater numbers of both CD11b(low) and CD11b(high) DC than with either cytokine alone, and these DC were more efficient at antigen (Ag) capture. The FL+pGM-CSF-generated CD11b(low) DC lacked expression of CD8alpha. Following treatment with LPS in vivo, all DC subsets upregulated CD40, CD80, CD86, and MHC class II expression, but surprisingly Ag capture was not downregulated and some DC subsets retained expression of intracellular MHC class II vesicles. Thus, even after activation in vivo with LPS, DC retained Ag capture properties of immature DC, and Ag presentation/costimulation properties of mature DC. Though all DC subsets stimulated CD4(+) T cell proliferation equivalently, FL-generated DC were more efficient at priming Ag-specific CD8(+) cytolytic T cells than DC generated with either pGM-CSF alone or FL+pGM-CSF, and CD11b(high) DC were more efficient at priming CD8(+) T cells than CD11b(low) DC.

  • role of hematopoietic growth factors Flt3 Ligand in expansion and regulation of dendritic cells
    Current Opinion in Hematology, 2001
    Co-Authors: Hilary J. Mckenna
    Abstract:

    Dendritic cells (DCs) are hematopoietic cells that initiate immune responses by presenting antigen to T cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a primary growth factor for DCs in vitro, but recently it was recognized that other factors including Flt3 Ligand (FL) and G-CSF expand various DC subsets in vivo. DCs undergo a complex series of maturation and activation steps after they acquire antigen and before they can activate resting T cells. In addition, they must traffic to T-cell-rich areas of lymph nodes (LN) to achieve this. Each of these steps is tightly regulated, and in the last year progress has been made in identifying some of the key molecules involved in each of these steps. This progress will further the efforts underway to develop DCs as vaccine adjuvants.

  • Role of hematopoietic growth factors/Flt3 Ligand in expansion and regulation of dendritic cells
    Current opinion in hematology, 2001
    Co-Authors: Hilary J. Mckenna
    Abstract:

    Dendritic cells (DCs) are hematopoietic cells that initiate immune responses by presenting antigen to T cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a primary growth factor for DCs in vitro, but recently it was recognized that other factors including Flt3 Ligand (FL) and G-CSF expand various DC subsets in vivo. DCs undergo a complex series of maturation and activation steps after they acquire antigen and before they can activate resting T cells. In addition, they must traffic to T-cell-rich areas of lymph nodes (LN) to achieve this. Each of these steps is tightly regulated, and in the last year progress has been made in identifying some of the key molecules involved in each of these steps. This progress will further the efforts underway to develop DCs as vaccine adjuvants.

  • In vivo generation of human dendritic cell subsets by Flt3 Ligand
    Blood, 2000
    Co-Authors: Eugene Maraskovsky, Dania Caron, Elizabeth Daro, Eileen R. Roux, Mark Teepe, Charlie Maliszewski, Jeannie Hoek, Mel E. Lebsack, Hilary J. Mckenna
    Abstract:

    Dendritic cells (DCs) represent a family of ontogenically distinct leukocytes involved in immune response regulation. The ability of DCs to stimulate T-cell immunity has led to their use as vectors for immunotherapy vaccines. However, it is unclear whether and to what degree in vitro-generated DCs are representative of DCs that develop in vivo. Treatment of mice with human Flt3 Ligand (FL) dramatically increases the number of DCs. We report here that administration of FL to healthy human volunteers increased the number of circulating CD11c(+ )IL-3Ralpha(low) DC (mean 44-fold) and CD11c(-) IL-3Ralpha(high) DC precursors (mean 12-fold). Moreover, the CD11c(+ )DCs were efficient stimulators of T cells in vitro. Thus, FL can expand the number of circulating, functionally competent human DCs in vivo.

  • Cloning of the human homologue of the murine Flt3 Ligand : a growth factor for early hematopoietic progenitor cells
    Blood, 1994
    Co-Authors: Sd Lyman, S. Escobar, L James, L Johnson, Kenneth Brasel, P De Vries, H. Downey, Rr Splett, M. P. Beckmann, Hilary J. Mckenna
    Abstract:

    Using a fragment of the murine Flt3 Ligand as a probe, we have succeeded in cloning a human Flt3 Ligand from a human T-cell lambda gt10 cDNA library. The human and murine Ligands are 72% identical at the amino acid level. Analysis of multiple cDNA clones shows that alternative splicing of the human Flt3 mRNA can occur at a number of positions. A recombinant soluble form of the human Flt3 Ligand stimulates the proliferation and colony formation of a subpopulation of human bone marrow cells that are CD34+ and are enriched for primitive hematopoietic cells. In addition, the human Flt3 Ligand also stimulates the proliferation of cells expressing murine Flt3 receptors. Northern blot analysis shows widespread expression of Flt3 Ligand mRNA transcripts in human tissues.

S D Lyman - One of the best experts on this subject based on the ideXlab platform.

  • Biologic effects and potential clinical applications of Flt3 Ligand.
    Current opinion in hematology, 1998
    Co-Authors: S D Lyman
    Abstract:

    Flt3 Ligand (FL) is a member of a small family of growth factors that stimulate the proliferation of hematopoietic cells by binding to and activating distinct tyrosine kinase receptors. Other members of this family include M-CSF and the c-kit Ligand. Expression of the Flt3 receptor is primarily restricted to the most primitive hematopoietic progenitor cells, and FL stimulates the proliferation in vitro and the expansion and mobilization in vivo of stem and progenitor cells. FL as a single factor has little proliferative activity on these stem and progenitor cells, but it synergizes with a wide range of other colony-stimulating factors and interleukins to stimulate proliferation of these cells. FL is also an effective agent for mobilizing stem and progenitor cells to peripheral blood. Recent data demonstrating anti-tumor activity of FL suggest that this protein plays a major role in activating the immune system via its ability to stimulate the production of both dendritic and natural killer cells. These biologic activities of FL may potentially prove quite useful in a number of clinical settings.

  • Structural analysis of human and murine Flt3 Ligand genomic loci.
    Oncogene, 1995
    Co-Authors: S D Lyman, K. Stocking, Barry L. Davison, Fletcher F, Johnson L, S. Escobar
    Abstract:

    Both the murine and human genomic loci that encode Flt3 Ligand have been cloned. Flt3 Ligand is a hematopoietic growth factor that stimulates the proliferation of stem and progenitor cells. The portions of the murine and human Flt3 Ligand genomic loci encompassing the coding region of the protein are approximately 4.0 kb and 5.9 kb, respectively. The human genomic locus is larger as a result of the presence of repeated sequences within introns I, II, IV, V and VI. The transmembrane isoform of the murine and human Flt3 Ligand proteins are each encoded within seven exons (1-5 + 7 and 8). Analyses of Flt3 Ligand cDNA clones show that alternative splicing of a putative sixth exon results in the generation of a soluble form of the Flt3 Ligand protein. The sizes of each of the exons are well conserved between species. Murine and human Flt3 genomic loci have a similar exon: intron structure compared to the genomic loci encoding Steel factor and colony stimulating factor 1. These proteins, which appear to be ancestrally related, are hematopoietic growth factors that stimulate cells via specific and structurally related tyrosine kinase receptors on the cell surface.

  • Identification of soluble and membrane-bound isoforms of the murine Flt3 Ligand generated by alternative splicing of mRNAs.
    Oncogene, 1995
    Co-Authors: S D Lyman, K. Stocking, S. Escobar, L James, P De Vries, H. Downey, M. P. Beckmann, I. Brasel, Neal G. Copeland, L. S. Cleveland
    Abstract:

    We have recently described a novel hematopoietic growth factor, referred to as the Flt3 Ligand, that stimulates the proliferation of sub-populations of hematopoietic cells that are enriched for stem and progenitor cells. This factor is a transmembrane protein that undergoes proteolytic cleavage to generate a soluble form of the protein. We have isolated additional Flt3 Ligand isoforms by PCR that contain an extra exon and encode what are predicted to be either a soluble form of the Ligand or a longer version of the transmembrane protein. We have also isolated cDNAs from murine T cell libraries that encode an isoform of the Flt3 Ligand that has an unusual C-terminus. This isoform results from a failure to splice out an intron during mRNA processing. The protein encoded by this cDNA is expressed on the cell surface, where it is biologically active. However, this novel isoform does not appear to give rise to a soluble form of the protein. Regulation of mRNA splicing is likely to control the generation of cell bound or soluble forms of this hematopoietic growth factor. Genetic mapping studies localize the gene encoding the Flt3 Ligand to the proximal portion of mouse chromosome 7 and to human chromosome 19q13.3.

  • Biology of Flt3 Ligand and receptor.
    International journal of hematology, 1995
    Co-Authors: S D Lyman
    Abstract:

    The Flt3 Ligand is a member of a small family of growth factors that stimulate the proliferation of hematopoietic cells; other members of this family include Steel factor (also known as mast cell growth factor, stem cell factor, and kit Ligand) and colony stimulating factor 1. These proteins function by binding to and activating unique tyrosine kinase receptors. Expression of the Flt3 receptor is primarily restricted among hematopoietic cells to the most primitive progenitor cells. The Flt3 Ligand is similar to Steel factor in that both proteins stimulate the proliferation of early progenitor or stem cells. Neither of these factors has much proliferative activity on its own, but each factor can synergize with a wide range of other colony stimulating factors and interleukins (ILs) to stimulate proliferation. One major difference between the two factors appears to be their effect on mast cells, which Steel factor stimulates but Flt3 Ligand does not. Although Flt3 Ligand and Steel factor each act on early hematopoietic cells, differences in their activities suggest that they are not redundant and both are required for normal hematopoiesis. There are a number of clinical settings in which the Flt3 Ligand may potentially prove quite useful.

  • Biology and potential clinical applications of Flt3 Ligand.
    Current opinion in hematology, 1995
    Co-Authors: S D Lyman, Douglas E. Williams
    Abstract:

    The Flt3 Ligand is a member of a small family of growth factors that stimulate the proliferation of hematopoietic cells. Other members of this family include Steel factor (also known as mast cell growth factor, stem cell factor, and kit Ligand) and colony-stimulating factor 1. These proteins function by binding to and activating unique tyrosine kinase receptors. Both Flt3 Ligand and Steel factor stimulate the proliferation of early progenitor or stem cells. Neither of these factors exhibits much biologic activity by itself, but each factor can synergize with a wide range of other colony-stimulating factors and interleukins. One major difference between the two factors appears to be their effect on mast cells, which Steel factor stimulates, but Flt3 Ligand does not. Although Flt3 Ligand and Steel factor each act on early hematopoietic cells, differences in their activities suggest that they are not redundant and are both required for normal hematopoiesis. There are a number of clinical settings in which the Flt3 Ligand may prove quite useful.