PU.1 regulates expression of the interleukin-7 receptor in lymphoid progenitors.

Development of the lymphoid system is dependent on the Ets family transcription factor PU.1. We demonstrate that PU.1(-/-) hematopoietic progenitors fail to express IL-7Ralpha transcripts. Promoter and chromatin crosslinking analyses suggest that PU.1 directly regulates transcription of the IL-7Ralpha gene. Retroviral transduction of IL-7Ralpha into PU.1(-/-) progenitors restores IL-7-dependent proliferation and induces, at low frequency, the generation of pro-B cells undergoing an apparently normal program of differentiation. Although the related factor Spi-B can substitute for PU.1 in early B cell development, it is not required. These results demonstrate that PU.1 functions to regulate early B cell development in part by controlling the expression of the IL-7Ralpha gene.

[1]  H. Sakano,et al.  Prf, a novel Ets family protein that binds to the PU.1 binding motif, is specifically expressed in restricted stages of B cell development. , 1999, International immunology.

[2]  J. Miyazaki,et al.  Interleukin 7 receptor-deficient mice lack gammadelta T cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[3]  S. Ziegler,et al.  Cloning of the human and murine interleukin-7 receptors: Demonstration of a soluble form and homology to a new receptor superfamily , 1990, Cell.

[4]  S. Goff,et al.  A safe packaging line for gene transfer: separating viral genes on two different plasmids , 1988, Journal of virology.

[5]  A. Sharpe,et al.  Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. , 1996, Immunity.

[6]  G. Nolan,et al.  Episomal vectors rapidly and stably produce high-titer recombinant retrovirus. , 1996, Human gene therapy.

[7]  T. Malek,et al.  Expression and function of the gamma c subunit of the IL-2, IL-4, and IL-7 receptors. Distinct interaction of gamma c in the IL-4 receptor. , 1995, Journal of immunology.

[8]  M. Owen,et al.  The interleukin‐7 receptor alpha chain transmits distinct signals for proliferation and differentiation during B lymphopoiesis. , 1996, The EMBO journal.

[9]  Jon C. Aster,et al.  Efficient and Rapid Induction of a Chronic Myelogenous Leukemia-Like Myeloproliferative Disease in Mice Receiving P210 bcr/abl-Transduced Bone Marrow , 1998 .

[10]  A. Aguzzi,et al.  Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis. , 1992, Genes & development.

[11]  K. Dorshkind,et al.  A stromal cell line from myeloid long-term bone marrow cultures can support myelopoiesis and B lymphopoiesis. , 1987, Journal of immunology.

[12]  M. Simon,et al.  SPI-B Activates Transcription via a Unique Proline, Serine, and Threonine Domain and Exhibits DNA Binding Affinity Differences from PU.1* , 1999, The Journal of Biological Chemistry.

[13]  T. Honjo,et al.  Organization and reorganization of immunoglobulin heavy-chain genes. , 1981, Cold Spring Harbor symposia on quantitative biology.

[14]  Steven F. Ziegler,et al.  Defective IL7R expression in T-B+NK + severe combined immunodeficiency , 1998, Nature Genetics.

[15]  D. Largaespada,et al.  Cloning of the Murine Thymic Stromal Lymphopoietin (Tslp) Receptor , 2000, The Journal of experimental medicine.

[16]  H. Karasuyama,et al.  A complex of glycoproteins is associated with VpreB/lambda 5 surrogate light chain on the surface of mu heavy chain-negative early precursor B cell lines , 1993, The Journal of experimental medicine.

[17]  Matthias Merkenschlager,et al.  Association of Transcriptionally Silent Genes with Ikaros Complexes at Centromeric Heterochromatin , 1997, Cell.

[18]  K. Sugamura,et al.  Expression of the mouse interleukin‐2 receptor γ chain in various cell populations of the thymus and spleen , 1994, European journal of immunology.

[19]  A. Strasser,et al.  Bcl-2 Can Rescue T Lymphocyte Development in Interleukin-7 Receptor–Deficient Mice but Not in Mutant rag-1 −/− Mice , 1997, Cell.

[20]  W. Leonard,et al.  Restoration of lymphoid populations in a murine model of X-linked severe combined immunodeficiency by a gene-therapy approach. , 1999, Blood.

[21]  S. Burdach,et al.  Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine , 1995, The Journal of experimental medicine.

[22]  F. Moreau-Gachelin,et al.  DNA binding specificities of Spi-1/PU.1 and Spi-B transcription factors and identification of a Spi-1/Spi-B binding site in the c-fes/c-fps promoter. , 1995, Oncogene.

[23]  Heinz Baumann,et al.  Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin , 2000, Nature Immunology.

[24]  David Baltimore,et al.  Organization and reorganization of immunoglobulin genes in A-MuLV-transformed cells: Rearrangement of heavy but not light chain genes , 1981, Cell.

[25]  R. Grosschedl,et al.  Coordinate regulation of B cell differentiation by the transcription factors EBF and E2A. , 1999, Immunity.

[26]  R. Grosschedl,et al.  Transcriptional regulation of early B‐lymphocyte differentiation , 2000, Immunological reviews.

[27]  GATA factor transgenes under GATA-1 locus control rescue germline GATA-1 mutant deficiencies. , 2000 .

[28]  F. Melchers,et al.  Changes in frequencies of clonable pre B cells during life in different lymphoid organs of mice. , 1993, Blood.

[29]  E. Scott,et al.  Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. , 1994, Science.

[30]  E. Rothenberg,et al.  Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage. , 1999, Development.

[31]  M. Mattei,et al.  Characterization of Spi-B, a transcription factor related to the putative oncoprotein Spi-1/PU.1 , 1992, Molecular and cellular biology.

[32]  I. Weissman,et al.  Identification of Clonogenic Common Lymphoid Progenitors in Mouse Bone Marrow , 1997, Cell.

[33]  C. Turck,et al.  Cloning and functional characterization of early B-cell factor, a regulator of lymphocyte-specific gene expression. , 1993, Genes & development.

[34]  S. Nishikawa,et al.  Functional participation of the IL-2 receptor gamma chain in IL-7 receptor complexes. , 1994, Science.

[35]  S. Neben,et al.  Defects in Hemopoietic Stem Cell Activity in Ikaros Mutant Mice , 1999, The Journal of experimental medicine.

[36]  E. Scott,et al.  PU.1 functions in a cell-autonomous manner to control the differentiation of multipotential lymphoid-myeloid progenitors. , 1997, Immunity.

[37]  C. Murre,et al.  Induction of Early B Cell Factor (EBF) and Multiple B Lineage Genes by the Basic Helix-Loop-Helix Transcription Factor E12 , 1998, The Journal of experimental medicine.

[38]  R. Grosschedl,et al.  Failure of B-cell differentiation in mice lacking the transcription factor EBF , 1995, Nature.

[39]  M. Simon,et al.  The Ets protein Spi-B is expressed exclusively in B cells and T cells during development , 1996, The Journal of experimental medicine.

[40]  N. Tanaka,et al.  The Common γ-Chain for Multiple Cytokine Receptors , 1995 .

[41]  J. D. Di Santo,et al.  In vivo roles of receptor tyrosine kinases and cytokine receptors in early thymocyte development. , 1998, Current opinion in immunology.

[42]  S. Orkin,et al.  Knock-in mutation of transcription factor GATA-3 into the GATA-1 locus: partial rescue of GATA-1 loss of function in erythroid cells. , 1998, Developmental biology.

[43]  J. Walsh,et al.  PU.1 regulates both cytokine‐dependent proliferation and differentiation of granulocyte/macrophage progenitors , 1998, The EMBO journal.

[44]  I. Weissman,et al.  Bcl-2 Rescues T Lymphopoiesis in Interleukin-7 Receptor–Deficient Mice , 1997, Cell.

[45]  David Baltimore,et al.  A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins , 1989, Cell.

[46]  A. Sharpe,et al.  The ikaros gene is required for the development of all lymphoid lineages , 1994, Cell.

[47]  L. Herzenberg,et al.  Fetal Liver , 1967, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[48]  L. Spain,et al.  T cell development in PU.1-deficient mice. , 1999, Journal of immunology.

[49]  R. Gerstein,et al.  The role of cytokine receptor signaling in lymphocyte development. , 1999, Current opinion in immunology.

[50]  T. Winkler,et al.  Interleukin-3 and interleukin-7 are alternative growth factors for the same B-cell precursors in the mouse. , 1995, Blood.

[51]  L. Garrett-Sinha,et al.  PU.1 and Spi-B are required for normal B cell receptor-mediated signal transduction. , 1999, Immunity.

[52]  K. Rajewsky,et al.  Analysis of the B-cell progenitor compartment at the level of single cells , 1994, Current Biology.

[53]  W. Leonard,et al.  Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. , 1995, Immunity.

[54]  Stephen L. Nutt,et al.  Commitment to the B-lymphoid lineage depends on the transcription factor Pax5 , 1999, Nature.

[55]  O. Lantz,et al.  Differential requirement for the transcription factor PU.1 in the generation of natural killer cells versus B and T cells. , 2001, Blood.

[56]  I. Weissman,et al.  A clonogenic common myeloid progenitor that gives rise to all myeloid lineages , 2000, Nature.

[57]  Harinder Singh,et al.  Gene targeting reveals a hierarchy of transcription factors regulating specification of lymphoid cell fates. , 1996, Current opinion in immunology.

[58]  T. Taniguchi,et al.  Organization of the murine and human interleukin-7 receptor genes: two mRNAs generated by differential splicing and presence of a type I-interferon-inducible promoter , 1991, Molecular and cellular biology.

[59]  H. Singh,et al.  PU.1, a shared transcriptional regulator of lymphoid and myeloid cell fates. , 1999, Cold Spring Harbor symposia on quantitative biology.

[60]  N. Patel,et al.  Evidence for stabilizing selection in a eukaryotic enhancer element , 2000, Nature.

[61]  C. Ware,et al.  Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice , 1994, The Journal of experimental medicine.

[62]  T. Taniguchi,et al.  Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development , 1993, Cell.

[63]  P. Farnham,et al.  c-Myc target gene specificity is determined by a post-DNAbinding mechanism. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[64]  A. Fischer,et al.  Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[65]  A. Brass,et al.  Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. , 1996, Genes & development.

[66]  A. Feeney,et al.  Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. , 1996, The EMBO journal.

[67]  T. Hawley,et al.  Versatile retroviral vectors for potential use in gene therapy. , 1994, Gene therapy.

[68]  S. Nishikawa,et al.  Expression and function of the interleukin 7 receptor in murine lymphocytes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[69]  M. Busslinger,et al.  Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus. , 1997, Genes & development.

[70]  A. Mårtensson,et al.  Spi-C, a Novel Ets Protein That Is Temporally Regulated during B Lymphocyte Development* , 1999, The Journal of Biological Chemistry.

[71]  E. Scott,et al.  A critical role for PU.1 in homing and long-term engraftment by hematopoietic stem cells in the bone marrow. , 1999, Blood.

[72]  S. Ziegler,et al.  Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. , 1993, Science.

[73]  A. Riddell,et al.  Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor , 1998, Nature.

[74]  K. Muegge,et al.  Interleukin-7: physiological roles and mechanisms of action. , 1999, Cytokine & growth factor reviews.

[75]  H. Weintraub,et al.  The helix-loop-helix gene E2A is required for B cell formation , 1994, Cell.

[76]  Ian Krop,et al.  E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements , 1994, Cell.

[77]  I. Weissman,et al.  Bcl-2 Rescues T Lymphopoiesis, but Not B or NK Cell Development, in Common γ Chain–Deficient Mice , 1997 .

[78]  R. Sen,et al.  ETS protein-dependent accessibility changes at the immunoglobulin mu heavy chain enhancer. , 1999, Immunity.

[79]  Irving L. Weissman,et al.  The Fetal Liver Counterpart of Adult Common Lymphoid Progenitors Gives Rise to All Lymphoid Lineages, CD45+CD4+CD3− Cells, As Well As Macrophages1 , 2001, The Journal of Immunology.

[80]  N. Tanaka,et al.  The common gamma-chain for multiple cytokine receptors. , 1995, Advances in immunology.

[81]  A. Rolink,et al.  Long‐term proliferating early pre B cell lines and clones with the potential to develop to surface Ig‐positive, mitogen reactive B cells in vitro and in vivo. , 1991, The EMBO journal.

[82]  H. Singh,et al.  Regulation of B lymphocyte and macrophage development by graded expression of PU.1. , 2000, Science.

[83]  Stephen L. Nutt,et al.  Commitment to the B-lymphoid lineage depends on the transcription factor Pax5 , 1999, Nature.