Autoregulation of interleukin 6 and granulocyte-macrophage colony-stimulating factor in the differentiation of myeloid leukemic cells.

Induction of differentiation in one type of clone of mouse myeloid leukemic cells by mouse or human interleukin 6 (IL-6) and in another type of clone by mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to be associated with induction of IL-6 and GM-CSF mRNA and protein. The results indicated that IL-6 and GM-CSF could positively autoregulate their own gene expression during myeloid cell differentiation. It is suggested that this autoregulation may serve to enhance and prolong the signal induced by these proteins in cells transiently exposed to IL-6 or GM-CSF.

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Induction of dependence on hematopoietic proteins for viability and receptor upregulation in differentiating myeloid leukemic cells

Blood ◽

10.1182/blood.v74.2.579.579 ◽

1989 ◽

Vol 74 (2) ◽

pp. 579-585 ◽

Cited By ~ 17

Author(s):

J Lotem ◽

L Sachs

Keyword(s):

Hormone Receptors ◽

Leukemic Cells ◽

Colony Stimulating Factor ◽

Surface Receptors ◽

Gm Csf ◽

Leukemic Clone ◽

Macrophage Colony Stimulating Factor ◽

Induction Of Differentiation ◽

Macrophage Colony ◽

Stimulating Factor

Abstract There are different types of myeloid leukemic cells that can be induced to differentiate to mature granulocytes or macrophages by different hematopoietic regulatory proteins. One type of leukemic clone can be induced to differentiate by recombinant macrophage and granulocyte differentiation-inducing protein-type 2 (MGI-2), which we have shown is Interleukin-6 (IL-6), and another type of leukemic clone can be differentiated by recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-3. There was no subpopulation of growth factor- responsive or differentiation-defective cells before induction of differentiation in either type of clone. In both clones, induction of differentiation-induced requirement for a hematopoietic protein for cell viability. Viability of the cells was maintained by IL-6, IL-3, or macrophage colony-stimulating factor (M-CSF) but not by GM-CSF in the cells differentiated by IL-6, and by GM-CSF or IL-3 but not by IL-6 or M-CSF in the cells differentiated by GM-CSF or IL-3. The viable cells with a differentiated phenotype continued to multiply. In undifferentiated leukemic cells with no or few surface receptors for some of these proteins, there was an upregulation of the number of receptors during differentiation for the proteins to which the cells responded. But there were also differentiating leukemic cells with an upregulation of GM-CSF receptors although GM-CSF could not maintain the viability of the differentiating cells. The results indicate that induction of hormone responsiveness and upregulation of the hormone receptors can both occur in differentiating leukemic cells, and that the regulation of these two events can be separated.

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Induction of dependence on hematopoietic proteins for viability and receptor upregulation in differentiating myeloid leukemic cells

Blood ◽

10.1182/blood.v74.2.579.bloodjournal742579 ◽

1989 ◽

Vol 74 (2) ◽

pp. 579-585 ◽

Cited By ~ 1

Author(s):

J Lotem ◽

L Sachs

Keyword(s):

Hormone Receptors ◽

Leukemic Cells ◽

Colony Stimulating Factor ◽

Surface Receptors ◽

Gm Csf ◽

Leukemic Clone ◽

Macrophage Colony Stimulating Factor ◽

Induction Of Differentiation ◽

Macrophage Colony ◽

Stimulating Factor

There are different types of myeloid leukemic cells that can be induced to differentiate to mature granulocytes or macrophages by different hematopoietic regulatory proteins. One type of leukemic clone can be induced to differentiate by recombinant macrophage and granulocyte differentiation-inducing protein-type 2 (MGI-2), which we have shown is Interleukin-6 (IL-6), and another type of leukemic clone can be differentiated by recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-3. There was no subpopulation of growth factor- responsive or differentiation-defective cells before induction of differentiation in either type of clone. In both clones, induction of differentiation-induced requirement for a hematopoietic protein for cell viability. Viability of the cells was maintained by IL-6, IL-3, or macrophage colony-stimulating factor (M-CSF) but not by GM-CSF in the cells differentiated by IL-6, and by GM-CSF or IL-3 but not by IL-6 or M-CSF in the cells differentiated by GM-CSF or IL-3. The viable cells with a differentiated phenotype continued to multiply. In undifferentiated leukemic cells with no or few surface receptors for some of these proteins, there was an upregulation of the number of receptors during differentiation for the proteins to which the cells responded. But there were also differentiating leukemic cells with an upregulation of GM-CSF receptors although GM-CSF could not maintain the viability of the differentiating cells. The results indicate that induction of hormone responsiveness and upregulation of the hormone receptors can both occur in differentiating leukemic cells, and that the regulation of these two events can be separated.

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Cytoplasmic Domains of the Human Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Receptor β Chain (hβc) Responsible for Human GM-CSF-induced Myeloid Cell Differentiation

Journal of Biological Chemistry ◽

10.1074/jbc.273.31.19411 ◽

1998 ◽

Vol 273 (31) ◽

pp. 19411-19418 ◽

Cited By ~ 16

Author(s):

Tetsuya Matsuguchi ◽

Michael B. Lilly ◽

Andrew S. Kraft

Keyword(s):

Cell Differentiation ◽

Myeloid Cell ◽

Colony Stimulating Factor ◽

Cytoplasmic Domains ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Β Chain ◽

Stimulating Factor

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Enhanced expression of the granulocyte-macrophage colony stimulating factor gene in acute myelocytic leukemia cells following in vitro blast cell enrichment

Blood ◽

10.1182/blood.v72.4.1329.bloodjournal7241329 ◽

1988 ◽

Vol 72 (4) ◽

pp. 1329-1332 ◽

Cited By ~ 1

Author(s):

DC Kaufman ◽

MR Baer ◽

XZ Gao ◽

ZQ Wang ◽

HD Preisler

Keyword(s):

T Cell ◽

Leukemic Cells ◽

Acute Myelocytic Leukemia ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Myelocytic Leukemia ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Expression of the granulocyte-macrophage colony-stimulating factor (GM- CSF) gene in acute myelocytic leukemia (AML) was assayed by Northern blot analysis. GM-CSF messenger RNA (mRNA) was detected in the freshly obtained mononuclear cells of only one of 48 cases of AML, in contrast with recent reports that GM-CSF mRNA might be detected in half of the cases of AML when RNA is prepared from T-cell- and monocyte-depleted leukemic cells. We did find, however, that expression of the GM-CSF gene was detectable in five of ten cases after in vitro T-cell and monocyte depletion steps. Additional studies suggest that expression of GM-CSF in the bone marrow of the one positive case, rather than being autonomous, was under exogenous control, possibly by a paracrine factor secreted by marrow stromal cells. These studies emphasize the potential for altering in vivo patterns of gene expression by in vitro cell manipulation.

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Role of Granulocyte-Macrophage Colony-Stimulating Factor in Acute Myeloid Leukemia/Myelodysplastic Syndromes

Journal of Global Oncology ◽

10.1200/jgo.2017.009332 ◽

2018 ◽

pp. 1-6

Author(s):

Neemat M. Kassem ◽

Alya M. Ayad ◽

Noha M. El Husseiny ◽

Doaa M. El-Demerdash ◽

Hebatallah A. Kassem ◽

...

Keyword(s):

Gene Expression ◽

Myeloid Leukemia ◽

Serum Levels ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Acute Myeloid

Purpose Granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine stimulates growth, differentiation, and function of myeloid progenitors. We aimed to study the role of GM-CSF gene expression, its protein, and antibodies in patients with acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) and their correlation to disease behavior and treatment outcome. The study included 50 Egyptian patients with AML/MDS in addition to 20 healthy volunteers as control subjects. Patients and Methods Assessment of GM-CSF gene expression was performed by quantitative real-time polymerase chain reaction. GM-CSF proteins and antibodies were assessed by enzyme-linked immunosorbent assay. Results There was significant decrease in GM-CSF gene expression ( P = .008), increase in serum level of GM-CSF protein ( P = .0001), and increase in anti–GM-CSF antibodies ( P = .001) in patients with AML/MDS compared with healthy control subjects. In addition, there was a significant negative correlation between serum levels of GM-CSF protein and initial peripheral blood blasts, percentage as well as response to therapy. Conclusion Any alteration in GM-CSF gene expression could have implications in leukemogenesis. In addition, GM-CSF protein serum levels could be used to predict outcome of therapy. GM-CSF antibodies may also play a role in the pathogenesis of AML/MDS. The use of these GM-CSF parameters for disease monitoring and as markers of disease activity needs further research.

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STAT5A-Deficient Mice Demonstrate a Defect in Granulocyte-Macrophage Colony-Stimulating Factor–Induced Proliferation and Gene Expression

Blood ◽

10.1182/blood.v90.5.1768 ◽

1997 ◽

Vol 90 (5) ◽

pp. 1768-1776 ◽

Cited By ~ 131

Author(s):

Gerald M. Feldman ◽

Louis A. Rosenthal ◽

Xiuwen Liu ◽

Mark P. Hayes ◽

Anthony Wynshaw-Boris ◽

...

Keyword(s):

Gene Expression ◽

Dna Binding Proteins ◽

Colony Stimulating Factor ◽

Wild Type ◽

Stat Proteins ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

In Cells

Abstract Responses of cells to cytokines typically involve the activation of a family of latent DNA binding proteins, referred to as signal transducers and activators of transcription (STAT) proteins, which are critical for the expression of early response genes. Of the seven known STAT proteins, STAT5 (originally called mammary gland factor) has been shown to be activated by several cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5, which are known to play important roles in growth and differentiation of hematopoietic precursors. In this report we have used mice that are deficient in STAT5A (one of two homologues of STAT5) to study the role of STAT5A in GM-CSF stimulation of cells. When bone marrow–derived macrophages were generated by differentiation with macrophage-CSF (M-CSF), exposure of cells from wild-type mice to GM-CSF resulted in a typical pattern of assembly of DNA binding proteins specific for the gamma activation sequence (GAS) element within the β-casein promoter. However, in cells from the STAT5A null mouse one of the shifted bands was absent. Immunoblotting analysis in the null mice showed that lack of STAT5A protein resulted in no alteration in activation of STAT5B by tyrosine phosphorylation. Proliferation experiments revealed that, when exposed to increasing concentrations of GM-CSF, cells derived from the null mice grew considerably more slowly than cells derived from the wild-type mice. Moreover, expression of GM-CSF–dependent genes, CIS and A1, was markedly inhibited in cells derived from null mice as compared with those of wild-type mice. The decreased expression observed with A1, a bcl-2 like gene, may account in part for the suppression of growth in cells from the null mice. These data suggest that the presence of STAT5A during the GM-CSF–induced assembly of STAT5 dimers is critical for the formation of competent transcription factors that are required for both gene expression and cell proliferation.

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The Human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF ) Receptor Exists as a Preformed Receptor Complex That Can Be Activated by GM-CSF, Interleukin-3, or Interleukin-5

Blood ◽

10.1182/blood.v90.8.3005 ◽

1997 ◽

Vol 90 (8) ◽

pp. 3005-3017 ◽

Cited By ~ 52

Author(s):

Joanna M. Woodcock ◽

Barbara J. McClure ◽

Frank C. Stomski ◽

Michael J. Elliott ◽

Christopher J. Bagley ◽

...

Keyword(s):

Myeloid Cell ◽

Cytokine Receptor ◽

Activation Mechanism ◽

Receptor Complex ◽

Colony Stimulating Factor ◽

Interleukin 3 ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Abstract The granulocyte-macrophage colony-stimulating factor (GM-CSF ) receptor is expressed on normal and malignant hematopoietic cells as well as on cells from other organs in which it transduces a variety of functions. Despite the widespread expression and pleiotropic nature of the GM-CSF receptor, little is known about its assembly and activation mechanism. Using a combination of biochemical and functional approaches, we have found that the human GM-CSF receptor exists as an inducible complex, analogous to the interleukin-3 (IL-3) receptor, and also as a preformed complex, unlike the IL-3 receptor or indeed other members of the cytokine receptor superfamily. We found that monoclonal antibodies to the GM-CSF receptor α chain (GMRα) and to the common β chain of the GM-CSF, IL-3, and IL-5 receptors (βc ) immunoprecipitated both GMRα and βc from the surface of primary myeloid cells, myeloid cell lines, and transfected cells in the absence of GM-CSF. Further association of the two chains could be induced by the addition of GM-CSF. The preformed complex required only the extracellular regions of GMRα and βc , as shown by the ability of soluble βc to associate with membrane-anchored GMRα or soluble GMRα. Kinetic experiments on eosinophils and monocytes with radiolabeled GM-CSF, IL-3, and IL-5 showed association characteristics unique to GM-CSF. Significantly, receptor phosphorylation experiments showed that not only GM-CSF but also IL-3 and IL-5 stimulated the phosphorylation of GMRα-associated βc . These results indicate a pattern of assembly of the heterodimeric GM-CSF receptor that is unique among receptors of the cytokine receptor superfamily. These results also suggest that the preformed GM-CSF receptor complex mediates the instantaneous binding of GM-CSF and is a target of phosphorylation by IL-3 and IL-5, raising the possibility that some of the biologic activities of IL-3 and IL-5 are mediated through the GM-CSF receptor complex.

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