Down-regulation of RXRalpha expression is essential for neutrophil development from granulocyte/monocyte progenitors.

Neutrophil granulocytes (Gs) represent highly abundant and short-lived leukocytes that are constantly regenerated from a small pool of myeloid committed progenitors. Nuclear receptor (NR) family members are ligand-activated transcription factors that play key roles in cellular proliferation and differentiation processes including myelopoiesis. Retinoid X receptor alpha (RXRalpha) represents the predominant NR types I and II homo- and heterodimerization partner in myeloid cells. Here we show that human myeloid progenitors express RXRalpha protein at sustained high levels during macrophage colony-stimulating factor (M-CSF)-induced monopoiesis. In sharp contrast, RXRalpha is down-regulated during G-CSF-dependent late-stage neutrophil differentiation from myeloid progenitors. Down-regulation of RXRalpha is critically required for neutrophil development since ectopic RXRalpha inhibited granulopoiesis by impairing proliferation and differentiation. Moreover, ectopic RXRalpha was sufficient to redirect G-CSF-dependent granulocyte differentiation to the monocyte lineage and to promote M-CSF-induced monopoiesis. Functional genetic interference with RXRalpha signaling in hematopoietic progenitor/stem cells using a dominant-negative RXRalpha promoted the generation of late-stage granulocytes in human cultures in vitro and in reconstituted mice in vivo. Therefore, our data suggest that RXRalpha down-regulation is a critical requirement for the generation of neutrophil granulocytes.

[1]  W. Ellmeier,et al.  Negative regulation of CD8 expression via Cd8 enhancer–mediated recruitment of the zinc finger protein MAZR , 2006, Nature Immunology.

[2]  H. Strobl,et al.  Differential involvement of PU.1 and Id2 downstream of TGF-beta1 during Langerhans-cell commitment. , 2006, Blood.

[3]  L. Altucci,et al.  Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor. , 2005, Cancer research.

[4]  H. Koeffler,et al.  Vitamin D compounds in leukemia , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[5]  J. Hamilton,et al.  cAMP inhibits CSF‐1‐stimulated tyrosine phosphorylation but augments CSF‐1R‐mediated macrophage differentiation and ERK activation , 2005, The FEBS journal.

[6]  H. Strobl,et al.  RelB regulates human dendritic cell subset development by promoting monocyte intermediates. , 2004, Blood.

[7]  W. Knapp,et al.  Myeloid cell-associated lysosomal proteins as flow cytometry markers for leukocyte lineage classification. , 2004, Journal of biological regulators and homeostatic agents.

[8]  P. Chambon,et al.  In vivo activation of PPAR target genes by RXR homodimers , 2004, The EMBO journal.

[9]  H. de Thé,et al.  PML–RARA-RXR Oligomers Mediate Retinoid and Rexinoid/cAMP Cross-Talk in Acute Promyelocytic Leukemia Cell Differentiation , 2004, The Journal of experimental medicine.

[10]  L. Altucci,et al.  Leukemia: beneficial actions of retinoids and rexinoids. , 2004, The international journal of biochemistry & cell biology.

[11]  P. Chambon,et al.  Retinoids Regulate Survival and Antigen Presentation by Immature Dendritic Cells , 2003, The Journal of experimental medicine.

[12]  S. Parmar,et al.  Acute promyelocytic leukaemia:a review , 2003, Expert opinion on pharmacotherapy.

[13]  Aristides G. Eliopoulos,et al.  Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells1 , 2003, The Journal of Immunology.

[14]  Bruce Blumberg,et al.  Active repression by unliganded retinoid receptors in development , 2003, The Journal of cell biology.

[15]  G. Hager,et al.  Dynamic Shuttling and Intranuclear Mobility of Nuclear Hormone Receptors* , 2003, The Journal of Biological Chemistry.

[16]  H. Koeffler,et al.  Normal myelopoiesis but abnormal T lymphocyte responses in vitamin D receptor knockout mice. , 2002, The Journal of clinical investigation.

[17]  S. Collins,et al.  The cytokines IL-3 and GM-CSF regulate the transcriptional activity of retinoic acid receptors in different in vitro models of myeloid differentiation. , 2002, Blood.

[18]  P. Kastner,et al.  Function of RARα during the maturation of neutrophils , 2001, Oncogene.

[19]  P. Chambon,et al.  Positive and negative regulation of granulopoiesis by endogenous RARalpha. , 2001, Blood.

[20]  N. Messaddeq,et al.  RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations. , 2001, Development.

[21]  S. Lehmann,et al.  Retinoid receptor expression and its correlation to retinoid sensitivity in non-M3 acute myeloid leukemia blast cells. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  Grace C. Lin,et al.  Dimerization with Retinoid X Receptors Promotes Nuclear Localization and Subnuclear Targeting of Vitamin D Receptors* , 2000, The Journal of Biological Chemistry.

[23]  P. Chambon,et al.  Skin abnormalities generated by temporally controlled RXRα mutations in mouse epidermis , 2000, Nature.

[24]  K. Ozato,et al.  ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. , 2000, Immunity.

[25]  I. Wang,et al.  Vitamin A deficiency in mice causes a systemic expansion of myeloid cells , 2000 .

[26]  T. Graf,et al.  MafB is an inducer of monocytic differentiation , 2000, The EMBO journal.

[27]  R. Andreesen,et al.  Expression of retinoid receptors during human monocyte differentiation in vitro. , 2000, Biochemical and biophysical research communications.

[28]  I. Bernstein,et al.  All-trans retinoic acid enhances the long-term repopulating activity of cultured hematopoietic stem cells. , 2000, Blood.

[29]  L. Altucci,et al.  RAR‐independent RXR signaling induces t(15;17) leukemia cell maturation , 1999, The EMBO journal.

[30]  V. Najfeld,et al.  Identification of novel chromosomal rearrangements in acute myelogenous leukemia involving loci on chromosome 2p23, 15q22 and 17q21 , 1999, Leukemia.

[31]  S. Collins,et al.  Retinoid X Receptor (RXR) Agonist-Induced Activation of Dominant-Negative RXR-Retinoic Acid Receptor α403 Heterodimers Is Developmentally Regulated during Myeloid Differentiation , 1999, Molecular and Cellular Biology.

[32]  H P Koeffler,et al.  Effects of novel RAR- and RXR-selective retinoids on myeloid leukemic proliferation and differentiation in vitro. , 1999, Blood.

[33]  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 .

[34]  C. Shayo,et al.  Forskolin induces U937 cell line differentiation as a result of a sustained cAMP elevation. , 1998, European journal of pharmacology.

[35]  S. Kitano,et al.  Transcriptional Regulation by Transforming Growth Factor β of the Expression of Retinoic Acid and Retinoid X Receptor Genes in Osteoblastic Cells Is Mediated through AP-1* , 1996, The Journal of Biological Chemistry.

[36]  R. Tsuyuoka,et al.  1,25-dihydroxyvitamin D3 differentiates normal neutrophilic promyelocytes to monocytes/macrophages in vitro. , 1996, Blood.

[37]  J. Rossi,et al.  Expression of Retinoid X Receptor α Is Increased upon Monocytic Cell Differentiation , 1996 .

[38]  N. Neamati,et al.  Activation of retinoid receptors RARα and RXRα induces differentiation and apoptosis, respectively, in HL-60 cells , 1996 .

[39]  M. Boehm,et al.  Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. , 1995, Journal of medicinal chemistry.

[40]  O. Majdic,et al.  Flow cytometric analysis of cell-surface and intracellular antigens in leukemia diagnosis. , 1994, Cytometry.

[41]  J. Vonesch,et al.  Genetic analysis of RXRα developmental function: Convergence of RXR and RAR signaling pathways in heart and eye morphogenesis , 1994, Cell.

[42]  R. Evans,et al.  RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. , 1994, Genes & development.

[43]  S. Collins,et al.  A dominant negative retinoic acid receptor blocks neutrophil differentiation at the promyelocyte stage. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[44]  K. Robertson,et al.  Multiple members of the retinoic acid receptor family are capable of mediating the granulocytic differentiation of HL-60 cells , 1992, Molecular and cellular biology.

[45]  K. Umesono,et al.  Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling , 1992, Nature.

[46]  C. E. van der Schoot,et al.  Monoclonal antibodies against myeloperoxidase are valuable immunological reagents for the diagnosis of acute myeloid leukaemia , 1990, British journal of haematology.

[47]  Zhen-yi Wang,et al.  Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. , 1988, Haematology and blood transfusion.

[48]  M. O'dorisio,et al.  Characterization of Cyclic Nucleotide Metabolism During Human Monocyte Differentiation , 1984, Journal of leukocyte biology.

[49]  P. Gaines,et al.  Retinoids in myelopoiesis. , 2003, Journal of biological regulators and homeostatic agents.

[50]  C. Teng,et al.  Lactoferrin gene expression and regulation: an overview. , 2002, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[51]  J. Cowland,et al.  Regulation of human neutrophil granule protein expression. , 2001, Current opinion in hematology.

[52]  P. Kastner,et al.  Function of RARalpha during the maturation of neutrophils. , 2001, Oncogene.

[53]  L. Nagy,et al.  Retinoid-induced apoptosis in normal and neoplastic tissues , 1998, Cell Death and Differentiation.

[54]  N. Neamati,et al.  Activation of retinoid receptors RAR alpha and RXR alpha induces differentiation and apoptosis, respectively, in HL-60 cells. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[55]  J. Rossi,et al.  Expression of Retinoid X Receptor alpha is increased upon monocytic cell differentiation. , 1996, Biochemical and biophysical research communications.