Interferon-γ-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles

Zhang, Weihua; Miyazato, Akira; Chen, Guibin; Kajigaya, Sachiko; Young, Neal S.; Maciejewski, Jaroslaw P.

doi:10.1182/blood-2005-05-1884

Cited by 115 publications

(95 citation statements)

References 50 publications

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“…Interestingly, the oncoprotein P210/BCR-ABL has also been reported to up-regulate a group of IFN-responsive genes (25). In addition, IFN-inducible genes are up-regulated in preleukemic conditions such as aplastic anemia, paroxysmal nocturnal hemoglobinuria, and MDS (26). Thus, induction of IFN pathways may reflect a common response during leukemogenesis.…”

Section: Initial Antiproliferative Effect Of Nup98-hoxa9mentioning

confidence: 98%

NUP98-HOXA9 Induces Long-term Proliferation and Blocks Differentiation of Primary Human CD34+ Hematopoietic Cells

2006

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NUP98-HOXA9, the chimeric protein resulting from the t(7;11)(p15;p15) chromosomal translocation, is a prototype of several NUP98 fusions that occur in myelodysplastic syndromes and acute myeloid leukemia. We examined its effect on differentiation, proliferation, and gene expression in primary human CD34 + hematopoietic cells. Colony-forming cell (CFC) assays in semisolid medium combined with morphologic examination and flow cytometric immunophenotyping revealed that NUP98-HOXA9 increased the numbers of erythroid precursors and impaired both myeloid and erythroid differentiation. In continuous liquid culture, cells transduced with NUP98-HOXA9 exhibited a biphasic growth curve with initial growth inhibition followed by enhanced long-term proliferation, suggesting an increase in the numbers of primitive self-renewing cells. This was confirmed by a dramatic increase in the numbers of long-term cultureinitiating cells, the most primitive hematopoietic cells detectable in vitro. To understand the molecular mechanisms underlying the effects of NUP98-HOXA9 on hematopoietic cell proliferation and differentiation, oligonucleotide microarray analysis was done at several time points over 16 days, starting at 6 hours posttransduction. The early growth suppression was preceded by up-regulation of IFNB1 and accompanied by marked up-regulation of IFN-induced genes, peaking at 3 days posttransduction. In contrast, oncogenes such as homeobox transcription factors, FLT3, KIT, and WT1 peaked at 8 days or beyond, coinciding with increased proliferation. In addition, several putative tumor suppressors and genes associated with hematopoietic differentiation were repressed at later time points. These findings provide a comprehensive picture of the changes in proliferation, differentiation, and global gene expression that underlie the leukemic transformation of human hematopoietic cells by NUP98-HOXA9. (Cancer Res 2006; 66(13): 6628-37)

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Section: Initial Antiproliferative Effect Of Nup98-hoxa9mentioning

confidence: 98%

NUP98-HOXA9 Induces Long-term Proliferation and Blocks Differentiation of Primary Human CD34+ Hematopoietic Cells

2006

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“…Such negative feedback of MSCs on the inflammatory response is particularly important since IFN␥ has also been linked to aplastic anemia. 31 At high levels, IFN␥ acts as a hematopoietic suppressor, 32,33 thus it would be undesirable for the BM to have an ongoing inflammatory reaction. Although speculative, these arguments are in line with the recent report of MSCs being significant to hematologic disorders.…”

Section: Discussionmentioning

confidence: 99%

Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-γ

Chan

Tang

Patel

et al. 2006

Blood

401

307

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“…27 PBMCs from 3 healthy controls were cultured with or without rATG or hATG for 24 hours, and total RNA was extracted with the RNeasy kit (Qiagen, Valencia, CA). RNA purity was assessed by spectrophotometry.…”

Section: Rna Preparation and Microarray Assaymentioning

confidence: 99%

Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro

Feng

Kajigaya

Solomou

et al. 2008

Blood

Self Cite

210

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IntroductionRegulatory T cells (Tregs) are implicated in the suppression of immune responses and the maintenance of tolerance. [1][2][3] Tregs are characterized by the surface expression of CD4 and the interleukin-2 (IL-2) receptor (CD25); a member of the forkhead family of transcription factors, FOXP3, is expressed in the nuclei of human and murine CD4 ϩ CD25 ϩ Treg, especially in human CD4 ϩ CD25 high populations. FOXP3 acts as a master regulator for cytokine production and is necessary for cell-cell contactdependent inhibition of effector T-cell activation by Treg. [4][5][6] FOXP3 expression is required for Treg development and confers suppressive function on peripheral CD4 ϩ CD25 ϩ Tregs. 7 Mice lacking the nuclear factor of activated T cells (NFAT1) showed an enhanced immune response, with a tendency toward the development of a late Th2-like response. 8 Recent studies indicate that NFAT1 induces FOXP3 expression by binding to its promoter, 9 and FOXP3 controls Treg function through cooperation with NFAT1. 10 Treg numbers are deficient in patients with active systemic lupus erythematosus 11 and type 1 diabetes. 12 In patients with autoimmune hepatitis, Tregs are depleted and FOXP3 expression is decreased. 13 Patients undergoing stem-cell transplantation have a low risk of developing graft-versus-host disease (GVHD) if the Treg graft content is high. 14 In patients with multiple sclerosis, although Treg numbers are consistent with those in healthy individuals, there is a marked decrease in their effector function. 15 We have recently reported that CD4 ϩ CD25 high FOXP3 ϩ Tregs are decreased in most patients with aplastic anemia (AA). 16 CD4 ϩ Tregs tend to be decreased in low-risk myelodysplastic syndrome (MDS) patients but increased in high-risk MDS patients and correlated with progression to aggressive subtypes of the disease. 17 There is evidence that Tregs have the ability to prevent the development of autoimmune diseases, 18 tumor immunity, 19 graft rejection, 20 and GVHD 21 in mouse models. In these animal models, transfer of Tregs can prevent the autoimmune phenotype that develops after Treg depletion. Infusion of Tregs in a minor antigen H60-mediated AA mice model aborted H60-specific T-cell expansion and prevented bone marrow destruction. 22 Immunosuppressive drugs, such as antithymocyte globulin (ATG) and cyclosporin A (CsA), are widely used to prevent or treat acute graft rejection in organ transplantation, 23 in conditioning for transplantation, and for the treatment of AA and other autoimmune diseases, and GVHD. 24 Because of the important roles of Treg in disease pathophysiology and treatment, the effects of these immunosuppressive drugs on the function or expansion of Treg might be clarified. ATG is a purified IgG fraction of sera from rabbits or horses that have been immunized with human thymocytes or T-cell lines. ATG depletes peripheral lymphocytes from the circulating pool through complement-dependent lysis or activation-associated apoptosis, 23,25 but its effect on Treg has not been fully ...

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Interferon-γ-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles

Cited by 115 publications

References 50 publications

NUP98-HOXA9 Induces Long-term Proliferation and Blocks Differentiation of Primary Human CD34+ Hematopoietic Cells

NUP98-HOXA9 Induces Long-term Proliferation and Blocks Differentiation of Primary Human CD34+ Hematopoietic Cells

Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-γ

Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro

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