Permissive role of thrombopoietin and granulocyte colony-stimulating factor receptors in hematopoietic cell fate decisions
            <i>in vivo</i>

Stoffel, Ruedi; Ziegler, Suzanne; Ghilardi, Nico; Ledermann, Birgit; Sauvage, Frédéric J. de; Skoda, Radek C.

doi:10.1073/pnas.96.2.698

Cited by 61 publications

(43 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In a prior study, we demonstrated that ectopic expression of the EPOR in myeloid 32D cells was associated with EPO-mediated development of myeloid differentiation characteristics including morphological features and expression of the primary granule protein MPO [32]. These results were consistent with those of other studies [33], suggesting that the lineage specificity of a cytokine-associated response can be mediated by activation of noncanonical receptors and/or signaling pathways [reviewed in [5][6][7][8]34]. Because the function of mature neutrophils depends on both its primary and secondary granule proteins, we examined if EPOR-mediated signaling could result in increased secondary granule protein gene expression in 32D cells.…”

supporting

confidence: 83%

Cytokine signals through STAT3 promote expression of granulocyte secondary granule proteins in 32D cells

Wang

Arcasoy

Watowich

et al. 2005

Experimental Hematology

View full text Add to dashboard Cite

Objective-In a previous study, we showed that activation of a transfected human erythropoietin receptor (EPOR) in the murine myeloid cell line 32D resulted in the development of morphologic features of granulocytic differentiation and expression of the neutrophil primary granule protein myeloperoxidase. We now studied if EPOR signaling could also mediate secondary granule protein gene expression and investigated the signal transduction requirements for induction of secondary granule gene expression in 32D cells. Materials and Methods-Wild-type and variant 32D cells expressing normal or chimeric EPORsor receptors for granulocyte colony-stimulating factor (G-CSFRs) were stimulated with EPO or G-CSF and the expression of granulocyte-specific genes was analyzed by Northern blot analysis. To determine the signaling mechanisms required for secondary granule protein gene induction, the activation of STAT pathways following growth factor stimulation was studied by Western blot analysis.Results-We found that EPO treatment of 32D cells engineered to express EPOR did not result in induction of the secondary granule protein genes encoding lactoferrin and 24p3 lipocalin, the mouse homolog of human N-Gal, or the myeloid transcription factor C/EBPε. Replacement of the intracellular domain of EPOR with the intracellular domain of G-CSFR in a chimeric receptor was associated with EPO-mediated induction of lactoferrin, 24p3 lipocalin, and C/EBPε genes. We found that STAT3 phosphorylation was mediated by the intracellular domain of G-CSFR, but not EPOR. Replacement of one or two of the STAT5 binding sites in the intracytoplasmic domain of the EPOR with STAT3 binding sites resulted in EPO-mediated STAT3 activation and a marked increase in the expression of the 24p3 lipocalin gene. Knockdown of STAT3 protein levels with siRNA caused significant decrease in 24p3 lipocalin gene induction.Conclusion-These results indicate that EPOR signaling cannot substitute for G-CSFR signaling to stimulate secondary granule protein gene expression in 32D cells. In addition, STAT3 is a critical mediator of 24p3 lipocalin gene expression in these cells.Granulocyte colony-stimulating factor (G-CSF), through the interaction with its receptor (G-CSFR), is the major hematopoietic growth factor regulating the production of neutrophils. The importance of G-CSF in the regulation of granulopoiesis has been underscored by the observation that mice deficient in the G-CSF or G-CSFR gene, or mice expressing a chimeric G-CSFR/EPOR (erythropoietin receptor), developed severe neutropenia [1][2][3] These studies and others, including those of different hematopoietic growth factors and receptors, have led to two different theories or models regarding the role of specific growth factors and their receptors in the process of lineage commitment and differentiation: the "instructive" or deterministic model, in which growth factors play a direct role in lineagespecific commitment and differentiation, and the "permissive," stochastic, or cell-autonomous model, in wh...

show abstract

supporting

confidence: 83%

Cytokine signals through STAT3 promote expression of granulocyte secondary granule proteins in 32D cells

Wang

Arcasoy

Watowich

et al. 2005

Experimental Hematology

View full text Add to dashboard Cite

show abstract

“…[39][40][41] Receptor chains would appear therefore not to be able to dictate particular patterns of commitment or maturation.…”

Section: Discussionmentioning

confidence: 99%

Differentiation commitment and regulator-specific granulocyte–macrophage maturation in a novel pro-B murine leukemic cell line

et al. 2000

View full text Add to dashboard Cite

The cloned pro-B-lymphocyte murine leukemic cell line GB2, was established from a leukemic Max41 x E -myc double transgenic mouse. Its Igh alleles are rearranged and its surface markers are primarily B-lymphoid, but a small proportion of the cells also express surface Gr-1 and some cells develop the morphology of maturing granulocytes. The cell line grows continuously in suspension culture without the addition of growth factors, but expresses mRNA for M-CSF, TPO and Flt-3-ligand. When stimulated in agar cultures by GM-CSF, G-CSF, M-CSF, IL-3, SCF, IL-6, leukemia inhibitory factor (LIF), IL-5 or IFN␥, GB2 cells generated blast colonies or colonies of maturing granulocytes and macrophages. There was a striking similarity in colony types, relative colony numbers and maturation of colony cells to those formed by normal bone marrow cells in response to the same stimuli. GB2 blast colony-forming cells exhibited self-renewal as well as an ability to form granulocytemacrophage colony-forming progeny, with evidence that a hierarchical sequence of clonogenic cells is generated in the cell line even after subcloning. Factor-specific maturation was clearly initiated by the action of the added growth factors. In contrast, FACS-sorting experiments showed that commitment to various types of colony-forming cell occurs in maintenance suspension cultures in the apparent absence of potentially relevant growth factors. Leukemia (2000) 14, 1785-1795.

show abstract

“…In other experiments, a human GM-CSF receptor transgene expressed in EPOR-null fetal liver cells was shown to be able to restore erythropoiesis when cells were stimulated by GM-CSF (Hisakawa et al, 2001). In an elegant experiment, the cytoplasmic domain of the G-CSFR was targeted to the c-MPL locus to create mice bearing a chimeric receptor (Stoffel et al, 1999). This chimeric receptor was able to functionally substitute for the c-MPL receptor, despite lacking the cytoplasmic component of the c-MPL receptor.…”

Section: Cytokines: Instructive or Permissive?mentioning

confidence: 99%

Cytokine receptors and hematopoietic differentiation

2007

View full text Add to dashboard Cite

Permissive role of thrombopoietin and granulocyte colony-stimulating factor receptors in hematopoietic cell fate decisions in vivo

Cited by 61 publications

References 36 publications

Cytokine signals through STAT3 promote expression of granulocyte secondary granule proteins in 32D cells

Cytokine signals through STAT3 promote expression of granulocyte secondary granule proteins in 32D cells

Differentiation commitment and regulator-specific granulocyte–macrophage maturation in a novel pro-B murine leukemic cell line

Cytokine receptors and hematopoietic differentiation

Contact Info

Product

Resources

About