Stromal Cells Provide Signals Different from Cytokines for STAT5 Activation in Hematopoietic Cells.

Abstract

ABSTRACT. After detachment from the stromal cells, hematopoietic stem cells are thought to differentiate to the cytokine-dependent stages where their growth and differentiation are promoted by these cytokines. To examine the stromal regulation of hematopoietic stem cells, we previously established a primitive hematopoietic stem-like cell line, THS119, whose growth was dependent on the bone marrow stromal cell line, TBR59, and from which IL-3-(THS119/IL-3) or IL-7-(THS119/IL-7) dependent cell lines were then generated. Using these cell lines, we examined the difference in signals mediated by the stromal cells and cytokines.The cytokine-dependent cell lines (THS119/IL-3 and THS119/IL-7) showed induction of STAT5 phosphorylation and target genes for STAT5 such as CIS, pim-1, p21 and bcl-xL upon addition of IL-3 or IL-7. IL-3 or IL-7 also induced STAT5 phosphorylation and STAT5 target genes of the stromal cell-dependent cell line, THS119, in the absence of stromal cells at levels similar to the cytokine-dependent cell lines. However, quite interestingly, TBR59 stromal cells could not induce STAT5 phosphorylation of THS119 cells, although they did induce STAT5 target genes in THS119 cells. In addition, the mRNAs for STAT5 target genes in THS119 cells on the stromal cells seemed to be more stable than those in the cytokine-dependent cell lines. Expression of the antiapoptotic genes bcl-2 and bcl-xL was higher in the stromal cell-dependent cell line than in the cytokine-dependent cell lines. These results suggested that stromal cells and cytokines may provide different signals for growth and differentiation of the hematopoietic cells.

Interleukin-7 Is a Survival Factor for CD4+ CD25+ T-Cells and Is Expressed by Diabetes-Suppressive Dendritic Cells

“…It is noteworthy that STAT5 is one of the transcription factors responsive to IL-7 (51)(52)(53)(54)(55)(56)(57). In this report, in addition to confirming the diabetessuppressive properties of iDCs as we have previously published (25), we demonstrate that, at least in the NOD mouse, treatment of NOD-derived T-cells with IL-7 in vitro results in an increase in the steady-state numbers of CD4 ϩ…”

STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells

“…Interestingly, we found that STAT5 could bind near the MCL1 gene, albeit without leading to its transcriptional activation (supplemental Figure 4), which is in agreement with the fact that IL-7 does not upregulate Mcl-1 protein in these cells (supplemental Figure 6). Genes upregulated by IL-7 in a STAT5-dependent manner in TAIL7 cells include HRH2, APOL4, and CA6, as well as, expectedly, OSM, IKZF4, PIM1, SOCS2, and CISH, [45][46][47][48][49] whereas among the top downregulated genes, we found BCL6, NLRP6, and IL10 ( Figure 5D; supplemental Figure 4). We validated these results by qPCR analysis of IL-7-treated TAIL7 cells in the presence or absence of S5i.…”

Thymic Stromal-Derived Lymphopoietin Induces Proliferation of Pre-B Leukemia and Antagonizes mTOR Inhibitors, Suggesting a Role for Interleukin-7Rα Signaling

“…IL-7Ra is expressed from the early pro-B through the early pre-B stage of B-cell development and may be a marker for the common lymphoid progenitor (11,28). Signal transduction through both IL-7R and TSLPR complexes ultimately results in the activation of signal transducer and activator of transcription (STAT) 5 and subsequent cell proliferation, but does so through different pathway intermediates: IL-7 signals through the Janus-activated kinase 1/3 (JAK1/3) kinases, whereas the TSLP-mediated signaling intermediates before STAT5 activation have not been fully elucidated (29)(30)(31).…”