PU.1 determines the self-renewal capacity of erythroid progenitor cells.

PU.1 is a hematopoietic-specific transcriptional activator that is absolutely required for the differentiation of B lymphocytes and myeloid-lineage cells. Although PU.1 is also expressed by early erythroid progenitor cells, its role in erythropoiesis, if any, is unknown. To investigate the relevance of PU.1 in erythropoiesis, we produced a line of PU.1-deficient mice carrying a green fluorescent protein reporter at this locus. We report here that PU.1 is tightly regulated during differentiation-it is expressed at low levels in erythroid progenitor cells and down-regulated upon terminal differentiation. Strikingly, PU.1-deficient fetal erythroid progenitors lose their self-renewal capacity and undergo proliferation arrest, premature differentiation, and apoptosis. In adult mice lacking one PU.1 allele, similar defects are detected following stress-induced erythropoiesis. These studies identify PU.1 as a novel and critical regulator of erythropoiesis and highlight the versatility of this transcription factor in promoting or preventing differentiation depending on the hematopoietic lineage.

[1]  M. Wolfe,et al.  Notch Signaling Augments T Cell Responsiveness by Enhancing CD25 Expression 1 , 2003, The Journal of Immunology.

[2]  Bruce E. Torbett,et al.  Regulation of neutrophil and eosinophil secondary granule gene expression by transcription factors C/EBPε and PU.1 , 2003 .

[3]  John Anastasi,et al.  Cooperative and antagonistic interplay between PU.1 and GATA-2 in the specification of myeloid cell fates. , 2002, Immunity.

[4]  B. Habermann,et al.  Apoptosis Protection by the Epo Target Bcl-XL Allows Factor-Independent Differentiation of Primary Erythroblasts , 2002, Current Biology.

[5]  G. Blobel,et al.  Inhibition of CBP-Mediated Protein Acetylation by the Ets Family Oncoprotein PU.1 , 2002, Molecular and Cellular Biology.

[6]  B. Wasylyk,et al.  The p53 tumour suppressor inhibits glucocorticoid‐induced proliferation of erythroid progenitors , 2002, EMBO Reports.

[7]  S. Orkin,et al.  Transcriptional regulation of erythropoiesis: an affair involving multiple partners , 2002, Oncogene.

[8]  Jiang Zhu,et al.  Hematopoietic cytokines, transcription factors and lineage commitment , 2002, Oncogene.

[9]  Hyun-Jun Lee,et al.  PU.1 regulates expression of the interleukin-7 receptor in lymphoid progenitors. , 2002, Immunity.

[10]  H. Beug,et al.  Establishment of normal, terminally differentiating mouse erythroid progenitors: molecular characterization by cDNA arrays , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  T. Shirai,et al.  Lineage switch induced by overexpression of Ets family transcription factor PU.1 in murine erythroleukemia cells. , 2001, Blood.

[12]  J. Ghysdael,et al.  SPI-1 transforming properties depend upon specifically activated forms of the EPOR , 2000, Oncogene.

[13]  T. Hoang,et al.  A Pentamer Transcriptional Complex Including tal-1 and Retinoblastoma Protein Downmodulates c-kit Expression in Normal Erythroblasts , 2000, Molecular and Cellular Biology.

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

[15]  M. Busslinger,et al.  Lineage commitment in lymphopoiesis. , 2000, Current opinion in immunology.

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

[17]  R. Maki,et al.  Transcription Factor PU.1 Is Necessary for Development of Thymic and Myeloid Progenitor-Derived Dendritic Cells1 , 2000, The Journal of Immunology.

[18]  L. Spain,et al.  PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells. , 2000, Blood.

[19]  C. Kellendonk,et al.  The glucocorticoid receptor is required for stress erythropoiesis. , 1999, Genes & development.

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

[21]  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.

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

[23]  N. Rekhtman,et al.  Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells. , 1999, Genes & development.

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

[25]  E. Scott,et al.  Role of PU.1 in Hematopoiesis , 1998, Stem cells.

[26]  H. Beug,et al.  Cooperation of Spi‐1/PU.1 with an activated erythropoietin receptor inhibits apoptosis and Epo‐dependent differentiation in primary erythroblasts and induces their Kit ligand‐dependent proliferation , 1997, The EMBO journal.

[27]  J. Licht,et al.  Transcription factors, normal myeloid development, and leukemia. , 1997, Blood.

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

[29]  Midori Yoshida,et al.  Overexpression of PU.1 induces growth and differentiation inhibition and apoptotic cell death in murine erythroleukemia cells. , 1997, Blood.

[30]  G. Cheng,et al.  Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation , 1997, Oncogene.

[31]  M. Atchison,et al.  PU.1 can participate in an active enhancer complex without its transcriptional activation domain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[32]  C. I. Smith,et al.  Cell specific expression of human Bruton's agammaglobulinemia tyrosine kinase gene (Btk) is regulated by Sp1- and Spi-1/PU.1-family members. , 1996, Oncogene.

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

[34]  A. Friedman,et al.  C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase promoter , 1996, Molecular and cellular biology.

[35]  W. Vainchenker,et al.  Spi-1/PU.1 transgenic mice develop multistep erythroleukemias , 1996, Molecular and cellular biology.

[36]  D. Tenen,et al.  CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter , 1996, Molecular and cellular biology.

[37]  D. Tenen,et al.  PU.1 (Spi-1) and C/EBP alpha regulate expression of the granulocyte-macrophage colony-stimulating factor receptor alpha gene , 1995, Molecular and cellular biology.

[38]  Stuart H. Orkin,et al.  An early haematopoietic defect in mice lacking the transcription factor GATA-2 , 1994, Nature.

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

[40]  J. Li,et al.  The LIM protein RBTN2 and the basic helix-loop-helix protein TAL1 are present in a complex in erythroid cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[41]  M. Klemsz,et al.  Hematopoietic lineage- and stage-restricted expression of the ETS oncogene family member PU.1. , 1993, Blood.

[42]  C. Murre,et al.  Ets proteins: new factors that regulate immunoglobulin heavy-chain gene expression , 1993, Molecular and cellular biology.

[43]  S. Nishikawa,et al.  Stage-specific expression of c-kit protein by murine hematopoietic progenitors. , 1993, Blood.

[44]  U. Storb,et al.  PU.1 is a component of a multiprotein complex which binds an essential site in the murine immunoglobulin lambda 2-4 enhancer , 1993, Molecular and cellular biology.

[45]  W. Kuehl,et al.  Differentiation of mouse erythroleukemia cells is blocked by late up-regulation of a c-myb transgene , 1990, Molecular and cellular biology.

[46]  M. Mattei,et al.  The putative oncogene Spi-1: murine chromosomal localization and transcriptional activation in murine acute erythroleukemias. , 1989, Oncogene.

[47]  S. Schuetze,et al.  A common site for immortalizing proviral integrations in Friend erythroleukemia: molecular cloning and characterization , 1989, Journal of virology.

[48]  F. Moreau-Gachelin,et al.  Spi-1 is a putative oncogene in virally induced murine erythroleukaemias , 1988, Nature.

[49]  S. Green,et al.  A versatile in vivo and in vitro eukaryotic expression vector for protein engineering , 1988, Nucleic Acids Res..

[50]  E. Scott,et al.  PU.1 supports proliferation of immature erythroid progenitors. , 2004, Leukemia research.

[51]  H Phillip Koeffler,et al.  Regulation of neutrophil and eosinophil secondary granule gene expression by transcription factors C/EBP epsilon and PU.1. , 2003, Blood.