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1.
Cancer Genet Cytogenet ; 184(1): 57-61, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18558291

ABSTRACT

Deletion of the long arm of chromosome 15 is known as a rare but recurrent chromosomal abnormality in myeloid malignancies. We report a novel case of minimally differentiated hypoplastic acute myeloid leukemia (AML M0) in a patient who initially had a normal karyotype, but clonal interstitial deletion of chromosome 15, del(15)(q11.2q22), coincided with increment of leukemic cells a year later. We also summarize 18 published cases with myeloid malignancies and this chromosomal abnormality.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 15 , Leukemia, Myeloid, Acute/genetics , Adult , Aged , Aged, 80 and over , Cell Differentiation , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Recurrence
2.
Blood ; 111(4): 2427-35, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18042797

ABSTRACT

Hepatic stellate cells are believed to play a key role in the development of liver fibrosis. Several studies have reported that bone marrow cells can give rise to hepatic stellate cells. We hypothesized that hepatic stellate cells are derived from hematopoietic stem cells. To test this hypothesis, we generated chimeric mice by transplantation of clonal populations of cells derived from single enhanced green fluorescent protein (EGFP)-marked Lin(-)Sca-1(+)c-kit(+)CD34(-) cells and examined the histology of liver tissues obtained from the chimeric mice with carbon tetrachloride (CCl(4))-induced injury. After 12 weeks of CCl(4) treatment, we detected EGFP(+) cells in the liver, and some cells contained intracytoplasmic lipid droplets. Immunofluorescence analysis demonstrated that 50% to 60% of the EGFP(+) cells were negative for CD45 and positive for vimentin, glial fibrillary acidic protein, ADAMTS13, and alpha-smooth muscle actin. Moreover, EGFP(+) cells isolated from the liver synthesized collagen I in culture. These phenotypes were consistent with those of hepatic stellate cells. The hematopoietic stem cell-derived hepatic stellate cells seen in male-to-male transplants revealed only one Y chromosome. Our findings suggest that hematopoietic stem cells contribute to the generation of hepatic stellate cells after liver injury and that the process does not involve cell fusion.


Subject(s)
Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/physiology , Liver/cytology , Liver/physiology , Animals , Flow Cytometry , Genes, Reporter , Green Fluorescent Proteins/genetics , Hematopoietic Stem Cell Transplantation , Liver/injuries , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic
3.
Cancer Sci ; 98(10): 1597-603, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17645774

ABSTRACT

Interleukin (IL)-6 plays pleiotropic roles in human hematopoiesis and immune responses by acting on not only the IL-6 receptor-alpha subunit (IL-6Ralpha)(+) but also IL-6Ralpha(-) hematopoietic progenitors via soluble IL-6R. The Notch ligand Delta-1 has been identified as an important modulator of the differentiation and proliferation of human hematopoietic progenitors. Here, it was investigated whether these actions of IL-6 are influenced by Delta-1. When CD34(+)CD38(-) hematopoietic progenitors were cultured with stem cell factor, flt3 ligand, thrombopoietin and IL-3, Delta-1, in combination with the IL-6R/IL-6 fusion protein FP6, increased the generation of glycophorin A(+) erythroid cells but counteracted the effects of IL-6 and FP6 on the generation of CD14(+) monocytic and CD15(+) granulocytic cells. Although freshly isolated CD34(+)CD38(-) cells expressed no or only low levels of IL-6Ralpha, its expression was increased in myeloid progenitors after culture but remained negative in erythroid progenitors. It was found that Delta-1 acted in synergy with FP6 to enhance the generation of erythroid cells from the IL-6Ralpha(-) erythroid progenitors. In contrast, Delta-1 antagonized the effects of IL-6 and FP6 on the development of monocytic and granulocytic cells, as well as CD14(-)CD1a(+) dendritic cells, from the IL-6Ralpha(+) myeloid progenitors. These results indicate that Delta-1 interacts differentially with gp130 activation in IL-6Ralpha(-) erythroid and IL-6Ralpha(+) myeloid progenitors. The present data suggest a divergent interaction between Delta-1 and gp130 activation in human hematopoiesis.


Subject(s)
Cytokine Receptor gp130/pharmacology , Dendritic Cells/metabolism , Erythroid Precursor Cells/metabolism , Membrane Proteins/pharmacology , Myeloid Progenitor Cells/metabolism , Receptors, Interleukin-6/metabolism , Receptors, Notch/metabolism , Cells, Cultured , Flow Cytometry , Granulocytes/metabolism , Humans , Interleukin-3/metabolism , Interleukin-6/metabolism , Intracellular Signaling Peptides and Proteins , Ligands , Monocytes/metabolism
4.
Int J Oncol ; 30(3): 549-55, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17273755

ABSTRACT

Receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) share a common beta subunit. We recently reported that GM-CSF acts in concert with transforming growth factor-beta1 (TGF-beta1) and Notch ligand Delta-1 (Delta-1) to promote the differentiation of human blood monocytes into Langerhans cells. In the present study, we examined whether IL-3, in place of GM-CSF, can induce the development of Langerhans cells from blood monocytes in the presence of TGF-beta1 and Delta-1, because the IL-3 receptor alpha chain was substantially expressed on monocytes. However, the generation of Langerhans cells was not obtained by the combination of IL-3, TGF-beta1 and Delta-1, even though GM-CSF and IL-3 exhibited a similar effect with respect to the differentiation of monocytes into macrophages and dendritic cells. The addition of GM-CSF to the culture supplemented with IL-3, TGF-beta1 and Delta-1 restored the differentiation of monocytes toward Langerhans cells. A microarray analysis revealed that a number of genes including Langerhans cell markers, E-cadherin and Langerin, were specifically expressed in cells from GM-CSF-containing cultures but not in those from IL-3-containing cultures. These data suggest that IL-3 can not replace GM-CSF to induce the differentiation of human monocytes into Langerhans cells in culture.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Interleukin-3/physiology , Langerhans Cells/cytology , Monocytes/metabolism , Cadherins/metabolism , Cell Differentiation , Flow Cytometry , Gene Expression Regulation , Humans , Interleukin-3/metabolism , Lipopolysaccharide Receptors/biosynthesis , Monocytes/cytology , Oligonucleotide Array Sequence Analysis , Phenotype , Transforming Growth Factor beta1/metabolism
5.
Int J Hematol ; 84(3): 220-3, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17050195

ABSTRACT

We describe a patient with low-titer cold agglutinin disease (CAD) who developed mixed-type autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenia following chicken pox infection. At least 1 year before admission to hospital, the patient had mild hemolytic anemia associated with low-titer cold agglutinins. A severe hemolytic crisis and thrombocytopenia (Evans' syndrome) occurred several days after infection with chicken pox, and the patient was referred to our hospital. Serological findings revealed the presence of both cold agglutinins and warm-reactive autoantibodies against erythrocytes, and the diagnosis was mixed-type AIHA. Following steroid therapy, the hemoglobin (Hb) level and platelet count improved. The patient was closely followed over a 10-year period with recurrent documented hemolysis after viral or bacterial infections. Warm-reactive autoantibodies have not been detected in the last 2 years, and only the immunoglobulin M anti-I cold agglutinins with a low titer and wide thermal amplitude have remained unchanged. Therefore, the patient has received at least 10 mg prednisolone daily to maintain a Hb level of 10 g/dL. To the best of our knowledge, no adult case of low-titer CAD that has evolved into mixed-type AIHA and Evans' syndrome after chicken pox infection has been previously reported in the literature.


Subject(s)
Anemia, Hemolytic, Autoimmune/drug therapy , Anti-Inflammatory Agents/administration & dosage , Chickenpox , Prednisolone/administration & dosage , Thrombocythemia, Essential/drug therapy , Anemia, Hemolytic, Autoimmune/blood , Anemia, Hemolytic, Autoimmune/complications , Anemia, Hemolytic, Autoimmune/etiology , Autoantibodies/blood , Chickenpox/blood , Chickenpox/etiology , Female , Follow-Up Studies , Hemoglobins/analysis , Humans , Immunoglobulin M/blood , Middle Aged , Platelet Count , Syndrome , Thrombocythemia, Essential/blood , Thrombocythemia, Essential/etiology
6.
Br J Haematol ; 135(2): 242-53, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16939493

ABSTRACT

Histone acetylation and deacetylation play fundamental roles in transcriptional regulation. We investigated the role of histone deacetylases (HDACs) in human adult haematopoiesis, using the structurally distinct HDAC inhibitors FK228 (depsipeptide) and Trichostatin A. When CD34+ cells were cultured with interleukin (IL)-3 or stem cell factor (SCF) + IL-3, FK228 (0.5 ng/ml) specifically enhanced the generation of immature erythroid cells with a CD36+ glycophorin A (GPA)low phenotype. In semisolid cultures, FK228 promoted the formation of erythroid colonies by CD34+ cells with IL-3 and SCF + IL-3. Furthermore, upon exposure to FK228, CD34+ cell-derived CD36+ GPA- cells were induced to form erythroid colonies with IL-3 alone. Conversely, FK228 inhibited the generation of CD36+ GPAhigh relatively mature erythroid cells from CD34+ cells in the presence of erythropoietin (EPO) and SCF + EPO. FK228 suppressed the EPO-mediated survival of CD36+ GPAlow/- and CD36+ GPAhigh cells and induced their apoptosis. Similar effects were observed for trichostatin A in the generation of erythroid cells in IL-3- and EPO-containing cultures. These data suggest that HDACs negatively regulate the IL-3-mediated growth of early erythroid precursors by suppressing their responsiveness to IL-3, while playing an important role in EPO-mediated differentiation and survival of erythroid precursors. Our data revealed that HDACs have diverse functions in human adult erythropoiesis.


Subject(s)
Erythropoiesis/physiology , Histone Deacetylases/physiology , Adult , Antigens, CD34/analysis , Cell Survival/drug effects , Cells, Cultured , Colony-Forming Units Assay , Depsipeptides/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Erythropoiesis/drug effects , Erythropoietin/pharmacology , Histone Deacetylase Inhibitors , Humans , Hydroxamic Acids/pharmacology , Interleukin-3/pharmacology , Recombinant Proteins/pharmacology , Reverse Transcriptase Polymerase Chain Reaction/methods , Stem Cell Factor/pharmacology
7.
Int J Oncol ; 27(3): 743-8, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16077924

ABSTRACT

Histone acetylation controls the expression of specific genes in eukaryotic cells. We investigated the role of histone deacetylases (HDACs) in the differentiation of human erythroid cells, using pharmacological approaches. When CD36+ erythroid precursor cells, generated from CD34+ cells with stem cell factor, flt-3 ligand, thrombopoietin, interleukin-3, interleukin-6, and erythropoietin, were cultured with an HDAC inhibitor FK228 (depsipeptide) at a specified dose in the presence of erythropoietin, their differentiation was inhibited, as determined by the expression of CD45 and glycophorin A. Addition of the same dose of FK228 to cultures did not affect the growth of CD36+ cells. Regardless of the presence or absence of FK228, cultured CD36+ cells displayed similar proliferation kinetics. Analysis of acetylated histones revealed that FK228 upregulated the acetylation status of histones H3 and H4 in CD36+ cells. The inhibition of CD36+ cell differentiation was restored by removal of FK228 from the culture, indicating that the modification of CD36+ cell differentiation by FK228 is reversible. Furthermore, interference with histone deacetylation by FK228 inhibited the generation of CD36+ erythroid cells from CD34+ hematopoietic progenitor cells. Our results indicate the possible involvement of HDACs in human erythropoiesis, especially the regulation of erythroid cell differentiation.


Subject(s)
Cell Differentiation/physiology , Erythroid Cells/metabolism , Histone Deacetylases/physiology , Acetylation/drug effects , CD36 Antigens/analysis , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Depsipeptides/pharmacology , Erythroid Cells/cytology , Erythroid Cells/drug effects , Erythropoietin/pharmacology , Flow Cytometry , Glycophorins/analysis , Histone Deacetylases/metabolism , Histones/metabolism , Humans , Leukocyte Common Antigens/analysis , Time Factors
8.
J Leukoc Biol ; 78(4): 921-9, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16037408

ABSTRACT

Human Langerhans cells (LCs) are of hematopoietic origin, but cytokine regulation of their development is not fully understood. Notch ligand Delta-1 is expressed in a proportion of the skin. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-beta1 (TGF-beta1) are also secreted in the skin. We report here that Delta-1, in concert with GM-CSF and TGF-beta1, induces the differentiation of human CD14(+) blood monocytes into cells that express LC markers: CD1a, Langerin, cutaneous lymphocyte-associated antigen, CC chemokine receptor 6, E-cadherin, and Birbeck granules. The resulting cells display phagocytic activity and chemotaxis to macrophage inflammatory protein-1alpha (MIP-1alpha). In response to CD40 ligand and tumor necrosis factor alpha, the cells acquire a mature phenotype of dendritic cells that is characterized by up-regulation of human leukocyte antigen (HLA)-ABC, HLA-DR, CD80, CD86, CD40, and CD54 and appearance of CD83. These cells in turn show chemotaxis toward MIP-1beta and elicit activation of CD8(+) T cells and T helper cell type 1 polarization of CD4(+) T cells. Thus, blood monocytes can give rise to LCs upon exposure to the skin cytokine environment consisting of Delta-1, GM-CSF, and TGF-beta1, which may be, in part, relevant to the development of human epidermal LCs. Our results extend the functional scope of Notch ligand delta-1 in human hematopoiesis.


Subject(s)
Langerhans Cells/cytology , Langerhans Cells/physiology , Lipopolysaccharide Receptors/blood , Membrane Proteins/physiology , Monocytes/cytology , Monocytes/physiology , Amyloid Precursor Protein Secretases , Aspartic Acid Endopeptidases , Basic Helix-Loop-Helix Transcription Factors/drug effects , Basic Helix-Loop-Helix Transcription Factors/genetics , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Polarity/physiology , Cells, Cultured , Chemotaxis/physiology , Endopeptidases/drug effects , Enzyme Inhibitors/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Homeodomain Proteins/drug effects , Homeodomain Proteins/genetics , Humans , Intracellular Signaling Peptides and Proteins , Langerhans Cells/drug effects , Ligands , Lipopolysaccharide Receptors/drug effects , Lipopolysaccharide Receptors/metabolism , Membrane Proteins/pharmacology , Monocytes/drug effects , Phenotype , Transcription Factor HES-1 , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/pharmacology , Transforming Growth Factor beta1
9.
Int J Oncol ; 26(3): 731-5, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15703830

ABSTRACT

Interleukin (IL)-4 and IL-10 have a wide variety of activities in the immune system. We re-evaluated the action of IL-4 and IL-10 on human blood monocytes, myeloid dendritic cell (DC1) precursors, using a serum-free culture system. Both IL-4 and IL-10 inhibited the survival of CD14+ monocytes supported by granulocyte-macrophage colony-stimulating factor in a dose-dependent manner. When IL-4 and IL-10 were combined, they had synergistic effects at low doses and induced a profound suppression of CD14+ monocyte survival. When the optimal timing was determined, the exposure to IL-4 and IL-10 for the initial 2 days was essential for suppression of survival of CD14+ monocytes. Annexin V/propidium iodide staining indicates that the suppression of CD14+ monocyte survival induced by IL-4 and IL-10 results from apoptosis. Tumor necrosis factor-alpha and lipopolysaccharide abrogated the effects of IL-4 and IL-10 on CD14+ monocytes, albeit incompletely. Thus, IL-4 in synergy with IL-10 negatively regulates the survival of DC1 precursor monocytes by inducing their apoptosis, which is modulated by factors such as tumor necrosis factor-alpha and lipopolysaccharide. Our data suggest the primary activities of IL-4 and IL-10 in DC1-mediated immune responses.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Survival , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Interleukin-10/pharmacology , Interleukin-4/pharmacology , Monocytes , Apoptosis , Cell Culture Techniques , Dendritic Cells , Dose-Response Relationship, Drug , Humans
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