Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells.

Ectopic delivery of HOXB4 elicits the expansion of engrafting hematopoietic stem cells (HSCs). We hypothesized that inhibition of tumor necrosis factor-alpha (TNF-alpha) signaling may be central to the self-renewal signature of HOXB4. Because HSCs derived from Fanconi anemia (FA) knockout mice are hypersensitive to TNF-alpha, we studied Fancc(-/-) HSCs to determine the physiologic effects of HOXB4 on TNF-alpha sensitivity and the relationship of these effects to the engraftment defect of FA HSCs. Overexpression of HOXB4 reversed the in vitro hypersensitivity to TNF-alpha of Fancc(-/-) HSCs and progenitors (P) and partially rescued the engraftment defect of these cells. Coexpression of HOXB4 and the correcting FA-C protein resulted in full correction compared with wild-type (WT) HSCs. Ectopic expression of HOXB4 resulted in a reduction in both apoptosis and reactive oxygen species in Fancc(-/-) but not WT HSC/P. HOXB4 overexpression was also associated with a significant reduction in surface expression of TNF-alpha receptors on Fancc(-/-) HSC/P. Finally, enhanced engraftment was seen even when HOXB4 was expressed in a time-limited fashion during in vivo reconstitution. Thus, the HOXB4 engraftment signature may be related to its effects on TNF-alpha signaling, and this pathway may be a molecular target for timed pharmacologic manipulation of HSC during reconstitution.

[1]  R. Kapur,et al.  Distinct roles of stress-activated protein kinases in Fanconi anemia-type C-deficient hematopoiesis. , 2009, Blood.

[2]  K. Miyamoto,et al.  Foxo3a is essential for maintenance of the hematopoietic stem cell pool , 2009 .

[3]  David A. Williams,et al.  Reciprocal relationship between O6-methylguanine-DNA methyltransferase P140K expression level and chemoprotection of hematopoietic stem cells. , 2008, Cancer research.

[4]  David A. Williams,et al.  Rapid lentiviral transduction preserves the engraftment potential of Fanca(-/-) hematopoietic stem cells. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[5]  B. Wood,et al.  High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector. , 2008, The Journal of clinical investigation.

[6]  David A. Williams,et al.  TNF-α induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells , 2007 .

[7]  H. Auer,et al.  HOXB4's road map to stem cell expansion , 2007, Proceedings of the National Academy of Sciences.

[8]  Weidong Wang.  Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins , 2007, Nature Reviews Genetics.

[9]  David A. Williams,et al.  Lentiviral vectors pseudotyped with murine ecotropic envelope: increased biosafety and convenience in preclinical research. , 2006, Experimental hematology.

[10]  B. Storer,et al.  Differential Effects of HOXB4 on Nonhuman Primate Short- and Long-Term Repopulating Cells , 2006, PLoS medicine.

[11]  Keisuke Ito,et al.  Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells , 2006, Nature Medicine.

[12]  David A. Williams,et al.  A rapid method for retrovirus-mediated identification of complementation groups in Fanconi anemia patients. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  M. Drutskaya,et al.  Inhibitory effects of tumor necrosis factor on hematopoiesis seen in vitro are translated to increased numbers of both committed and multipotent progenitors in TNF-deficient mice. , 2005, Experimental hematology.

[14]  C. Mathew,et al.  A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M , 2005, Nature Genetics.

[15]  刘金明,et al.  IL-13受体α2降低血吸虫病肉芽肿的炎症反应并延长宿主存活时间[英]/Mentink-Kane MM,Cheever AW，Thompson RW，et al//Proc Natl Acad Sci U S A , 2005 .

[16]  M. L. Beau,et al.  Ex vivo culture of Fancc-/- stem/progenitor cells predisposes cells to undergo apoptosis, and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy. , 2005, Blood.

[17]  S. Carotta,et al.  HOXB4 enforces equivalent fates of ES-cell-derived and adult hematopoietic cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  G. Margison,et al.  Enhanced in vivo selection of bone marrow cells by retroviral-mediated coexpression of mutant O6-methylguanine-DNA-methyltransferase and HOXB4. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[19]  Marcella Mori,et al.  Gene expression in response to ionizing radiation: an overview of molecular features in hematopoietic cells. , 2004, Journal of biological regulators and homeostatic agents.

[20]  J. Krosl,et al.  In vitro expansion of hematopoietic stem cells by recombinant TAT-HOXB4 protein , 2003, Nature Medicine.

[21]  P. Romeo,et al.  Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein , 2003, Nature Medicine.

[22]  S. Karlsson,et al.  Enforced adenoviral vector-mediated expression of HOXB4 in human umbilical cord blood CD34+ cells promotes myeloid differentiation but not proliferation. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[23]  V. Poggi,et al.  TNF-alpha and IFN-gamma are overexpressed in the bone marrow of Fanconi anemia patients and TNF-alpha suppresses erythropoiesis in vitro. , 2003, Blood.

[24]  A. Rimek,et al.  High-level ectopic HOXB4 expression confers a profound in vivo competitive growth advantage on human cord blood CD34+ cells, but impairs lymphomyeloid differentiation. , 2003, Blood.

[25]  Marianne Berwick,et al.  A 20-year perspective on the International Fanconi Anemia Registry (IFAR). , 2003, Blood.

[26]  H. Broxmeyer,et al.  Retroviral-mediated expression of recombinant Fancc enhances the repopulating ability of Fancc-/- hematopoietic stem cells and decreases the risk of clonal evolution. , 2003, Blood.

[27]  G. Sauvageau,et al.  Deregulated expression of HOXB4 enhances the primitive growth activity of human hematopoietic cells. , 2002, Blood.

[28]  G. Sauvageau,et al.  HOXB4-Induced Expansion of Adult Hematopoietic Stem Cells Ex Vivo , 2002, Cell.

[29]  I. Dybedal,et al.  Self-Renewal of Multipotent Long-Term Repopulating Hematopoietic Stem Cells Is Negatively Regulated by FAS and Tumor Necrosis Factor Receptor Activation , 2001, The Journal of experimental medicine.

[30]  I. Dybedal,et al.  Tumor necrosis factor (TNF)-mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells. , 2001, Blood.

[31]  S. Olson,et al.  The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality. , 2001, Blood.

[32]  G. Bagby,et al.  FANCC interacts with Hsp70 to protect hematopoietic cells from IFN‐γ/TNF‐α‐mediated cytotoxicity , 2001 .

[33]  S. Ganesan,et al.  Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. , 2001, Molecular cell.

[34]  U. Thorsteinsdóttir,et al.  Enhanced in vivo regenerative potential of HOXB4-transduced hematopoietic stem cells with regulation of their pool size. , 1999, Blood.

[35]  T. Enver,et al.  A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal. , 1999, Genes & development.

[36]  K. Abel,et al.  Design of 5′ Untranslated Sequences in Retroviral Vectors Developed for Medical Use , 1999, Journal of Virology.

[37]  M. Buchwald,et al.  Loss of FancC Function Results in Decreased Hematopoietic Stem Cell Repopulating Ability , 1999, Blood.

[38]  M. Buchwald,et al.  Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac-/- mice. , 1998, Blood.

[39]  Gordon Royle,et al.  Inactivation of the Fanconi anemia group C gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells. , 1997, Blood.

[40]  C. McKerlie,et al.  Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia , 1996, Nature Genetics.

[41]  U. Thorsteinsdóttir,et al.  Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. , 1995, Genes & development.

[42]  B. Aggarwal,et al.  Characterization of the in vitro and in vivo species preference of human and murine tumor necrosis factor-alpha. , 1988, Cancer research.

[43]  W. Fiers,et al.  Species specificity of human and murine tumor necrosis factor. A comparative study of tumor necrosis factor receptors. , 1986, The Journal of biological chemistry.

[44]  W. Fiers,et al.  Recombinant tumor necrosis factor: species specificity for a variety of human and murine transformed cell lines. , 1986, Cellular immunology.

[45]  D. Arthur,et al.  Mitomycin C test for diagnostic differentiation of idiopathic aplastic anemia and Fanconi anemia. , 1981, Pediatrics.

[46]  S. Latt,et al.  Induction by alkylating agents of sister chromatid exchanges and chromatid breaks in Fanconi's anemia. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[47]  David A. Williams,et al.  References Subscriptions Permissions Email Alerts Inflammatory Reactive Oxygen Species-Mediated Hemopoietic Suppression in Fancc-Deficient Mice , 2013 .

[48]  D. Gjertson,et al.  TNFα blockade in human diseases : An overview of efficacy and safety , 2008 .

[49]  D. Gjertson,et al.  TNFalpha blockade in human diseases: an overview of efficacy and safety. , 2008, Clinical immunology.

[50]  David A. Williams,et al.  TNF-alpha induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells. , 2007, The Journal of clinical investigation.

[51]  David A. Williams,et al.  Stem cell collection and gene transfer in Fanconi anemia. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[52]  R. Humphries,et al.  Overexpression of HOXB4 confers a myelo-erythroid differentiation delay in vitro , 2005, Leukemia.

[53]  T. Enver,et al.  The lineage commitment and self-renewal of blood stem cells. , 2001 .

[54]  L. Zon.  Hematopoiesis : a developmental approach , 2001 .

[55]  G. Bagby,et al.  FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity. , 2001, The EMBO journal.