Transcription factor Gfi-1 induced by G-CSF is a negative regulator of CXCR4 in myeloid cells.

The mechanisms underlying granulocyte-colony stimulating factor (G-CSF)-induced mobilization of granulocytic lineage cells from the bone marrow to the peripheral blood remain elusive. We provide evidence that the transcriptional repressor growth factor independence-1 (Gfi-1) is involved in G-CSF-induced mobilization of granulocytic lineage cells from the bone marrow to the peripheral blood. We show that in vitro and in vivo G-CSF promotes expression of Gfi-1 and down-regulates expression of CXCR4, a chemokine receptor essential for the retention of hematopoietic stem cells and granulocytic cells in the bone marrow. Gfi-1 binds to DNA sequences upstream of the CXCR4 gene and represses CXCR4 expression in myeloid lineage cells. As a consequence, myeloid cell responses to the CXCR4 unique ligand SDF-1 are reduced. Thus, Gfi-1 not only regulates hematopoietic stem cell function and myeloid cell development but also probably promotes the release of granulocytic lineage cells from the bone marrow to the peripheral blood by reducing CXCR4 expression and function.

[1]  T. Nagasawa,et al.  Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. , 2006, Immunity.

[2]  M. de la Luz Sierra,et al.  G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells. , 2006, Blood.

[3]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[4]  Tong-Yuan Yang,et al.  The Gfi-1B Proto-Oncoprotein Repressesp21WAF1 and Inhibits Myeloid Cell Differentiation , 1998, Molecular and Cellular Biology.

[5]  K. Zsebo,et al.  In vivo stimulation of granulopoiesis by recombinant human granulocyte colony-stimulating factor. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Link,et al.  G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. , 2005, Blood.

[7]  A. Usheva,et al.  Carboxyl-terminal Src kinase homologous kinase negatively regulates the chemokine receptor CXCR4 through YY1 and impairs CXCR4/CXCL12 (SDF-1alpha)-mediated breast cancer cell migration. , 2005, Cancer research.

[8]  Hui Zeng,et al.  Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1 , 2002, Nature Genetics.

[9]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[10]  T. Nakahata,et al.  Exclusive expression of G‐CSF receptor on myeloid progenitors in bone marrow CD34+ cells , 2000, British journal of haematology.

[11]  A. V. Gulino.  WHIM syndrome: a genetic disorder of leukocyte trafficking , 2003, Current opinion in allergy and clinical immunology.

[12]  L. Druhan,et al.  Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia. , 2005, Blood.

[13]  J. Lévesque,et al.  Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. , 2003, The Journal of clinical investigation.

[14]  J. Cowell,et al.  Cloning and characterization of the TATA-less promoter from the human GFI1 proto-oncogene. , 2000, Annals of human genetics.

[15]  Fan Dong,et al.  Increased CCAAT Enhancer-binding Protein ϵ (C/EBPϵ) Expression and Premature Apoptosis in Myeloid Cells Expressing Gfi-1 N382S Mutant Associated with Severe Congenital Neutropenia* , 2006, Journal of Biological Chemistry.

[16]  T. Möröy,et al.  The Transcriptional Repressor Gfi1 Affects Development of Early, Uncommitted c-Kit+ T Cell Progenitors and CD4/CD8 Lineage Decision in the Thymus , 2003, The Journal of experimental medicine.

[17]  D. Link,et al.  Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. , 1996, Immunity.

[18]  J. Sodroski,et al.  The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry , 1996, Nature.

[19]  S. Arber,et al.  ERM is required for transcriptional control of the spermatogonial stem cell niche , 2005, Nature.

[20]  Booki Min,et al.  Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation. , 2002, Immunity.

[21]  S. Holly,et al.  The unique N-terminus of R-ras is required for Rac activation and precise regulation of cell migration. , 2005, Molecular biology of the cell.

[22]  T. Betsuyaku,et al.  Characterization of hematopoietic progenitor mobilization in protease-deficient mice. , 2004, Blood.

[23]  Y. Gazitt,et al.  Plasma Levels of SDF‐1 and Expression of SDF‐1 Receptor on CD34+ Cells in Mobilized Peripheral Blood of Non‐Hodgkin's Lymphoma Patients , 2001, Stem cells.

[24]  S. Orkin,et al.  Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells , 2004, Nature.

[25]  Takashi Nagasawa,et al.  Cellular niches controlling B lymphocyte behavior within bone marrow during development. , 2004, Immunity.

[26]  A R Dunn,et al.  Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. , 1994, Blood.

[27]  Scott Cameron,et al.  Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. , 2003, Immunity.

[28]  A. Fauci,et al.  USF/c-Myc enhances, while Yin-Yang 1 suppresses, the promoter activity of CXCR4, a coreceptor for HIV-1 entry. , 1999, Journal of immunology.

[29]  H. Moch,et al.  Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL , 2003, Nature.

[30]  T. Springer,et al.  The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. , 1999, Immunity.

[31]  R. Gorlin,et al.  Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease , 2003, Nature Genetics.

[32]  P. Farnham,et al.  Identification of unknown target genes of human transcription factors using chromatin immunoprecipitation. , 2002, Methods.

[33]  D. Zhuang,et al.  Increased CCAAT enhancer-binding protein epsilon (C/EBPepsilon) expression and premature apoptosis in myeloid cells expressing Gfi-1 N382S mutant associated with severe congenital neutropenia. , 2006, The Journal of biological chemistry.

[34]  H. Nakshatri,et al.  Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion , 2007, Oncogene.

[35]  D. Leduc,et al.  Leukocyte Elastase Negatively Regulates Stromal Cell-derived Factor-1 (SDF-1)/CXCR4 Binding and Functions by Amino-terminal Processing of SDF-1 and CXCR4* , 2002, The Journal of Biological Chemistry.

[36]  Zhijun Duan,et al.  Targets of the transcriptional repressor oncoprotein Gfi-1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[37]  George Eliopoulos,et al.  Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2 , 2003, Nature Genetics.

[38]  C. Overall,et al.  Matrix Metalloproteinase Activity Inactivates the CXC Chemokine Stromal Cell-derived Factor-1* , 2001, The Journal of Biological Chemistry.

[39]  Fred Schaper,et al.  The zinc finger protein Gfi‐1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3 , 2000, The EMBO journal.

[40]  D. Scadden,et al.  CXCR-4 Desensitization Is Associated with Tissue Localization of Hemopoietic Progenitor Cells1 , 2001, The Journal of Immunology.

[41]  M. Freedman,et al.  Novel Point Mutation in the Extracellular Domain of the Granulocyte Colony-Stimulating Factor (G-Csf) Receptor in a Case of Severe Congenital Neutropenia Hyporesponsive to G-Csf Treatment , 1999, The Journal of experimental medicine.

[42]  R. Taichman,et al.  G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4 , 2002, Nature Immunology.

[43]  Hui Zeng,et al.  Transcription factor Gfi1 regulates self‐renewal and engraftment of hematopoietic stem cells , 2004, The EMBO journal.

[44]  H. Nakshatri,et al.  NF-κ B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4* , 2003, Journal of Biological Chemistry.

[45]  Edward J. Fuchs,et al.  Pharmacokinetics and Safety of AMD-3100, a Novel Antagonist of the CXCR-4 Chemokine Receptor, in Human Volunteers , 2000, Antimicrobial Agents and Chemotherapy.

[46]  D. Link,et al.  G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. , 2002, Immunity.

[47]  I. Touw,et al.  Multiple Signals Mediate Proliferation, Differentiation, and Survival from the Granulocyte Colony-stimulating Factor Receptor in Myeloid 32D Cells* , 1999, The Journal of Biological Chemistry.

[48]  D. Link,et al.  STAT-3 activation is required for normal G-CSF-dependent proliferation and granulocytic differentiation. , 2001, Immunity.

[49]  M. Parmentier,et al.  Genomic organization and promoter characterization of human CXCR4 gene 1 , 1998, FEBS letters.

[50]  D. Tweardy,et al.  Cytokine-dependent granulocytic differentiation. Regulation of proliferative and differentiative responses in a murine progenitor cell line. , 1987, Journal of immunology.

[51]  Lei Yao,et al.  Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1. , 2002, Blood.

[52]  S. Orkin,et al.  Zinc-finger transcription factor Gfi-1: versatile regulator of lymphocytes, neutrophils and hematopoietic stem cells , 2006, Current opinion in hematology.

[53]  R. Paroni,et al.  Human CD34(+) cells express CXCR4 and its ligand stromal cell-derived factor-1. Implications for infection by T-cell tropic human immunodeficiency virus. , 1999, Blood.

[54]  S. Rankin,et al.  Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. , 2003, Immunity.

[55]  R. DePinho,et al.  STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. , 2002, Immunity.

[56]  Ari Elson,et al.  Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells , 2006, Nature Medicine.