BACKGROUND: It is well known that harmonious interactions among adhesion molecules and stromal cell-derived factor-1 (SDF-1)-mediated chemoattraction signalling via CXCR4 are needed for bone marrow homing of hematopoietic stem cells and progenitor cells. The aim of this study was to define the role of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta 1 (TFG-beta1), known as hematopoiesis-inhibitory cytokines, in the regulation of the molecules in relation to the homing. METHODS: We investigated the effects of these cytokines on the expression of CXCR4 and adhesion molecules and the production of SDF-1 in bone marrow cells including CD34+ cells, bone marrow endothelial cells (BMEC-1 cells), and bone marrow stromal cells (BMSCs). We also examined whether the cytokines influence in vitro transmigration of hematopoietic progenitors. RESULTS: None of the cytokines influenced CXCR4 expression on CD34+ cells or SDF-1- mediated chemotaxis of the cells. IFN-gamma and TNF-alpha, but not TGF-beta up-regulated the expression of L-selectin, ICAM-1, and VLA-4 on CD34+ cells. However, the up-regulation was not translated into the enhanced transendothelial migration. IFN-gamma and TNF-alpha up-regulated the expression of VCAM-1 and ICAM-1 on BMEC-1 cells, and rendered the endothelium more suitable for transendothelial migration of hematopoietic progenitors. IFN-gamma and TNF-alpha also up-regulated the expression of VCAM-1 and ICAM-1 on primary human BMSCs. All three cytokines significantly attenuated SDF-1 production from primary BMSCs, and TNF-alpha diminished SDF-1 production from BMEC-1 cells. CONCLUSION: These data indicate that IFN-gamma, TNF-alpha, and TGF-beta1 play a role in the regulation of bone marrow homing of hematopoietic cells via up-regulation of adhesion molecule expression and down-modulation of SDF-1 production in bone marrow cells.
Bone Marrow Cells* ; Bone Marrow* ; Chemotaxis ; Cytokines ; Endothelial Cells ; Endothelium ; Hematopoietic Stem Cells ; Humans* ; Integrin alpha4beta1 ; Intercellular Adhesion Molecule-1 ; Interferon-gamma* ; L-Selectin ; Mesenchymal Stromal Cells ; Stem Cells ; Transendothelial and Transepithelial Migration ; Transforming Growth Factor beta ; Transforming Growth Factor beta1 ; Tumor Necrosis Factor-alpha* ; Up-Regulation ; Vascular Cell Adhesion Molecule-1

BACKGROUND: Vascular endothelial growth factor (VEGF) is a multifunctional cytokine involved in angiogenesis as selective mitogen for endothelial cells as well as potent permeability factor. And interleukin-6 (IL-6) is also known to be a growth factor of myeloma cells. To determine the role of angiogenesis, VEGF and IL-6 in the patients with multiple myeloma, the relationship between the level of VEGF expression, microvessel count (MVC), IL-6 expression in the bone marrow specimen of multiple myeloma patients and stage, response, survival duration were evaluated in 18 patients with multiple myeloma who underwent bone marrow biopsy. METHODS: VEGF expression, MVC and IL-6 expression were assessed by immunohistochemical stain with polyclonal antibody to VEGF, factor VIII related antigen and IL-6 respectively. RESULTS: VEGF expression was higher in multiple myeloma than that of control (61.4+/-34.4% vs 19.0+/-25.9%, P<0.001), and MVC was also higher in multiple myeloma than that of control (11.7+/-6.1 vs 6.2+/-3.8, P=0.005). IL-6 was expressed in 66.7% of multiple myeloma but not in control (P<0.001). Between high VEGF expression group and low VEGF expression group, there were no significant differences in the stage, response or survival. There were no significant differences between hypervascular group and hypovascular group. Also IL-6 expression was not a prognostic indicator. After treatment, VEGF expression, MVC and IL- 6 expression were decreased in the responder, but these differences were not statistically significant (P=0.23, P=0.07, P=0.06), probably due to limited number of cases. CONCLUSION: VEGF, angiogenesis and IL-6 can play a role in the pathogenesis of multiple myeloma. But we cannot confirm the prognostic role of those parameters. Further study with more cases in longer duration as well as prospective study would be necessary for the establishment of relationship between VEGF expression, neovascularization, IL-6 expression and disease severity and prognosis of multiple myeloma.
Biopsy ; Bone Marrow ; Endothelial Cells ; Humans ; Interleukin-6* ; Microvessels ; Multiple Myeloma* ; Permeability ; Prognosis ; Vascular Endothelial Growth Factor A* ; von Willebrand Factor

Chronic neutrophilic leukemia is a rare myeloproliferative disorder. We have experienced a typical case of chronic neutrophilic leukemia in a 76-year-old man who complained abdominal distension due to hepatosplenomegaly. White blood cell count of peripheral blood was 50,500/nL with 90% segmented neutrophils. The underlying disease for a leukemoid reaction had not been detected. Leukocyte alkaline phosphatase score and the serum levels of vitamin B12 and uric acid were elevated. Chromosome study showed a normal karyotype without Philadelphia chromosome or bcr/abl rearrangement. Phorbol myristate acetate-activated respiratory burst activity of neutrophils measured with chemiluminescence showed increased activity.
Aged ; Alkaline Phosphatase ; Humans ; Karyotype ; Leukemia, Neutrophilic, Chronic* ; Leukemoid Reaction ; Leukocyte Count ; Leukocytes ; Luminescence ; Myeloproliferative Disorders ; Myristic Acid ; Neutrophils* ; Philadelphia Chromosome ; Respiratory Burst* ; Uric Acid ; Vitamin B 12

No abstract available.
Drug Therapy* ; Multiple Myeloma* ; Stem Cell Transplantation* ; Stem Cells*

Background: Nilotinib is a tyrosine kinase inhibitor approved by the Ministry of Food and Drug Safety for frontline and 2nd line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). This study aimed to confirm the safety and efficacy of nilotinib in routine clinical practice within South Korea. Methods: An open-label, multicenter, single-arm, 12-week observational post-marketing surveillance (PMS) study was conducted on 669 Korean adult patients with Ph + CML from December 24, 2010, to December 23, 2016. The patients received nilotinib treatment in routine clinical practice settings. Safety was evaluated by all types of adverse events (AEs) during the study period, and efficacy was evaluated by the complete hematological response (CHR) and cytogenetic response. Results: During the study period, AEs occurred in 61.3% (410 patients, 973 events), adverse drug reactions (ADRs) in 40.5% (271/669 patients, 559 events), serious AEs in 4.5% (30 patients, 37 events), and serious ADRs in 0.7% (5 patients, 8 events). Furthermore, unexpected AEs occurred at a rate of 6.9% (46 patients, 55 events) and unexpected ADRs at 1.2% (8 patients, 8 events). As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was achieved in 85.8% (139/162 patients). Conclusion This PMS study shows consistent results in terms of safety and efficacy compared with previous studies. Nilotinib was well tolerated and efficacious in adult Korean patients with Ph + CML in routine clinical practice settings.