Tag Archives: ABL

The mechanisms underlying granulocyte-colony stimulating factor (G-CSF)-induced mobilization of granulocytic lineage

The mechanisms underlying granulocyte-colony stimulating factor (G-CSF)-induced mobilization of granulocytic lineage cells from your bone marrow to the peripheral blood remain elusive. Gfi-1 binds to DNA sequences upstream of the gene and represses CXCR4 manifestation in myeloid lineage cells. As a consequence myeloid cell reactions to the CXCR4 unique ligand MEK162 SDF-1 are reduced. Thus Gfi-1 not only regulates hematopoietic stem cell function and myeloid cell development but also probably promotes the release of granulocytic lineage cells from your bone marrow to the peripheral blood by reducing CXCR4 manifestation and function. Intro The generation of neutrophils from hematopoietic precursors and their launch to the peripheral blood circulation are highly controlled processes that make sure the maintenance of homeostatic neutrophil levels in the blood and their rise in response to bacterial infections and other signals. Granulocyte-colony stimulating element (G-CSF) has emerged as a critical regulator of granulopoiesis because mice transporting homozygous deletions of G-CSF or its receptor are seriously neutropenic 1 2 and dominant-negative mutations of granulocyte colony-stimulating element receptor (G-CSFR) have been linked to severe problems of granulopoiesis.3 4 In addition administration of G-CSF induces an expansion of myeloid lineage cells in the bone marrow and promotes the release of neutrophils and hematopoietic progenitor cells from your bone marrow to the peripheral blood.5 On the basis of these properties G-CSF is widely used to induce granulopoiesis and to mobilize hematopoietic progenitors to the peripheral blood. The biologic activities of G-CSF are solely mediated by its activation of the G-CSFR that is indicated on myeloid lineage progenitor cells.6 Compelling evidence from genetic studies and other studies showed that G-CSF indirectly promotes hematopoietic MEK162 cell and neutrophil mobilization to the peripheral blood by modulating the activities of the chemokine SDF-1 its receptor CXCR4 or both which are essential for the retention of hematopoietic cells to the bone marrow cavity.7-12 AMD3100 a competitive inhibitor of SDF-1 binding to its receptor and a mutant form of SDF-1β which induces prolonged down-regulation of the CXCR4 surface receptor promote the mobilization of neutrophils and hematopoietic cells to the peripheral blood.13 14 Osteoblasts stromal cells and endothelial cells constitutively communicate SDF-1 in the bone marrow; hematopoietic cells communicate CXCR4.15 16 During stem-cell mobilization with G-CSF SDF-1 and CXCR4 protein levels decrease in the bone MEK162 marrow.7-11 To explain such reductions some studies have supported a role for MEK162 enzymatic cleavage of SDF-1 or CXCR4 or both by metalloproteinase-9 neutrophil elastase and cathepsin-G 10 17 18 but mice deficient of these enzymes responded normally to G-CSF mobilization.8 Other studies indicated that G-CSF transcriptionally down-regulates SDF-1 expression in the bone marrow acting indirectly on osteoblasts that do not communicate G-CSFR.19 We have recently reported that G-CSF MEK162 reduces CXCR4 expression in MEK162 bone marrow Gr-1+ myeloid cells which communicate G-CSFR.20 This is consistent with earlier observations that CXCR4 levels are reduced on neutrophils and CD34+ hematopoietic progenitor cells recently released from your bone marrow to the peripheral blood.21 22 In the current study we display that G-CSF promotes the manifestation of the transcriptional repressor growth factor independence-1 (Gfi-1) in cells of myeloid lineage in vitro and in vivo and that Gfi-1 represses transcription. The ABL transcription element Gfi-1 is essential for granulocytic lineage maturation during development23-25 and for maintenance of the hematopoietic stem- cell pool postnatally.26 27 Thus the results described here increase understanding of the molecular mechanisms responsible for G-CSF-induced mobilization of myeloid cells from your bone marrow to the peripheral blood and lengthen the spectrum of activities of the Gfi-1 repressor. Materials and methods Cells The murine IL-3-dependent 32Dcl3 cell collection28 (a gift of Dr Alan D. Friedman Johns Hopkins University or college) was managed in Iscove-modified Dulbecco medium (Mediatech; Cellgro Herndon VA) comprising 10% heat-inactivated fetal bovine serum (FBS;.