scholarly journals Tumor Necrosis Factor Polymorphism Affects Transplantation Outcome in Patients with Myelodysplastic Syndrome but Not in Those with Chronic Myelogenous Leukemia, Independent of the Presence of HLA-DR15

2010 ◽  
Vol 16 (12) ◽  
pp. 1700-1706 ◽  
Author(s):  
Laura F. Newell ◽  
Ted Gooley ◽  
John A. Hansen ◽  
Derek L. Stirewalt ◽  
Effie W. Petersdorf ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Myelodysplastic Syndrome ◽  
Chronic Myelogenous Leukemia ◽  
Tumor Necrosis ◽  
Myelogenous Leukemia ◽  
Necrosis Factor

Elevated circulating levels of tumor necrosis factor predict unresponsiveness to treatment with interferon alfa-2b in chronic myelogenous leukemia.

1992 ◽  
Vol 10 (4) ◽  
pp. 631-634 ◽  
Author(s):  
F Herrmann ◽  
S G Helfrich ◽  
A Lindemann ◽  
E Schleiermacher ◽  
C Huber ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Chronic Myelogenous Leukemia ◽  
Tumor Necrosis ◽  
Performance Status ◽  
Chronic Phase ◽  
Serum Levels ◽  
Myelogenous Leukemia ◽  
Serum Samples ◽  
Circulating Levels ◽  
Necrosis Factor

PURPOSE The study was undertaken to analyze circulating tumor necrosis factor (TNF) levels in patients with chronic-phase chronic myelogenous leukemia (CML) undergoing interferon (IFN) alfa-2b therapy, and to correlate pretreatment serum levels of TNF with response to IFN alfa-2b therapy. PATIENTS AND METHODS Fourteen patients with CML in chronic phase were treated with recombinant human IFN alfa-2b for 7 to 39 months. RESULTS In eight patients IFN alfa-2b treatment failed due to lack of hematologic response. A complete or partial hematologic remission was achieved in the remaining six patients, of whom two patients experienced a complete cytogenetic response. Retrospective analysis of serum samples obtained from all patients before the onset of IFN alfa-2b administration revealed that levels (mean +/- SEM) of circulating TNF were higher (P less than .001) in the group of patients who did not respond to IFN alfa-2b treatment (157 +/- 15 U/mL) than in the responders (10.3 +/- 4 U/mL) or healthy control subjects (9.1 +/- 3 U/mL). However, there was no correlation between TNF serum levels and other patient characteristics at study enrollment including age, sex, duration of disease, performance status, splenomegaly, WBC count, platelet count, hemoglobin value, prior therapy, and prognostic category. CONCLUSION These findings indicate that circulating levels of TNF are increased in a subset of patients with chronic-phase CML and that this elevation is associated with poor response to IFN alfa-2b therapy.

scholarly journals Endogenous Tumor Necrosis Factor as a Predictor of Doxorubicin Sensitivity in Leukemic Patients

Blood ◽  
1997 ◽  
Vol 89 (7) ◽  
pp. 2472-2479 ◽  
Author(s):  
Daisuke Kobayashi ◽  
Naoki Watanabe ◽  
Naofumi Yamauchi ◽  
Naoki Tsuji ◽  
Tsutomu Sato ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Lymphoblastic Leukemia ◽  
Acquired Resistance ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Acute Myelogenous ◽  
Established Cell ◽  
Mnsod Activity ◽  
Necrosis Factor

Abstract We have previously reported that intracellular tumor necrosis factor (enTNF ) is responsible for resistance, in established cell lines to doxorubicin (DOX), exogenous TNF, and heat stress by inducing manganous superoxide dismutase (MnSOD), thereby scavenging reactive oxygen free radicals. Leukemic cells from 19 patients (6 acute lymphoblastic leukemia, 13 acute myeloid leukemia) were examined for their sensitivity to DOX and TNF in relation to their enTNF expression and MnSOD activity. Sensitivity to DOX and the expression of enTNF or MnSOD activity were inversely correlated. In a case with acquired resistance to chemotherapy which included DOX, enTNF expression and MnSOD activity were increased. Furthermore, in 14 cases treated with a regimen including an anthracycline, 4 cases that failed to respond to chemotherapy showed relatively high amounts of enTNF expression. KG-1 (human acute myelogenous leukemia) cells transfected with a nonsecretory-type TNF expression vector (pTNFΔpro) showed resistance to DOX. A significant increase in MnSOD levels was also noted in the transfectants. TNF antisense cDNA was transfected into isolated leukemic cells from five patients. Sensitivity of the antisense transfectants to DOX was increased, approximately 1.4- to 2.5-fold. These results suggest that enTNF acts as a resistance factor against DOX in leukemia, and that enTNF may be useful as a predictor of DOX sensitivity in leukemia.

scholarly journals Functional expression of c-kit by acute myelogenous leukemia blasts is enhanced by tumor necrosis factor-alpha through posttranscriptional mRNA stabilization by a labile protein

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1224-1230 ◽  
Author(s):  
MA Brach ◽  
HJ Buhring ◽  
HJ Gruss ◽  
LK Ashman ◽  
WD Ludwig ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Tumor Necrosis Factor ◽  
Mrna Expression ◽  
Half Life ◽  
Tumor Necrosis ◽  
Myelogenous Leukemia ◽  
Tnf Alpha ◽  
Kit Gene ◽  
Acute Myelogenous ◽  
Necrosis Factor

Abstract The c-kit proto-oncogene encodes a transmembrane glycoprotein identical to the receptor for the recently cloned stem cell factor (SCF). The present study examines constitutive synthesis of transcripts in primary acute myelogenous leukemia (AML) blasts and the effects of recombinant human tumor necrosis factor (TNF)-alpha on c-kit mRNA expression in these cells. The c-kit transcripts were detectable at low levels in 10 of 10 different AML samples investigated. TNF treatment of AML cells was associated with enhanced c-kit mRNA expression in all specimens. Nuclear run-on transcription assays indicated that the c-kit gene was transcriptionally active in all leukemias examined and the rate of transcription was unaffected by exposure to TNF, suggesting posttranscriptional control mechanisms of c-kit mRNA accumulation. In the absence of TNF, the half-life of c-kit transcripts was 2 to 3 hours, while in TNF-treated AML cells, c-kit half-life was found to be 5 to 9 hours. Inhibition of protein synthesis reduced TNF-induced c-kit mRNA expression by Northern blot analysis, but did not affect the rate of c-kit gene transcription. In the presence of inhibition of protein synthesis, the half-life of c-kit transcripts in TNF-induced leukemia cells decreased to 2 to 4 hours. These findings indicate that levels of c-kit mRNA are controlled by a labile protein that is involved in TNF- mediated stabilization of c-kit transcripts. The effects of TNF-alpha also extended to the protein level in that TNF-alpha treatment of primary AMLs was associated with enhanced surface expression of the SCF receptor by some of these cells. While exogenous SCF induced clonogenic growth of all primary AML samples investigated, TNF-alpha failed to stimulate leukemic cells to proliferate. However, the combination of SCF and TNF-alpha resulted in synergistic growth stimulation in seven of nine different AML specimens investigated. The finding of transmodulation of the SCF receptor through posttranscriptional modifications might further contribute to our understanding of the synergistic interplay of TNF-alpha and SCF.

scholarly journals Antileukemic effect of recombinant tumor necrosis factor alpha in vitro and its modulation by alpha and gamma interferons

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 728-738
Author(s):  
M Beran ◽  
KB McCredie ◽  
MJ Keating ◽  
JU Gutterman
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Suspension Cultures ◽  
Myelogenous Leukemia ◽  
Necrosis Factor Alpha ◽  
Ifn Gamma ◽  
Ifn Alpha ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Clonogenic Cells

The effect of recombinant human tumor necrosis factor alpha (rTNF- alpha) on human myelogenous leukemia clonogenic cells growing either in semisolid media or in suspension cultures was studied and compared with the effect on normal granulocyte-macrophage progenitors (GM-CFC). Exposure of cells to a range of rTNF-alpha doses including pharmacologically achievable plasma concentrations revealed a large heterogeneity in the response of leukemic clonogenic growth to rTNF- alpha. Only one of 13 specimens was highly resistant to rTNF-alpha. Eight of ten leukemic samples were significantly more sensitive than were normal GM-CFC, particularly within the in vivo achievable dose range (1 x 10(0) to 1 x 10(2) ng/mL). No significantly increased inhibition of either normal or leukemic clonogenic growth could be achieved by increasing the rTNF-alpha concentration above 250 ng/mL. Proliferation of leukemic clonogenic cells (L-CFC) was studied in suspension cultures. In five cases the clonogenic cells were significantly inhibited by rTNF-alpha while in one case no inhibition was observed. The inhibition of L-CFC growth by rTNF-alpha was dose dependent between 1 x 10(0) and 1 x 10(2) ng/mL. In suspension cultures, the TNF effect on L-CFC was a function of time of exposure, particularly with low concentrations of TNF. A remarkably higher inhibition of L-CFC as compared with the total leukemic population was observed in suspension cultures. Stimulation of L-CFC growth by rTNF- alpha was not observed. Normal GM-CFC were inhibited by alpha and gamma interferons (INF-alpha, -gamma) in a dose-related manner, with higher sensitivity of colonies than clusters. The response of GM-CFC to combination of recombinant IFNs and TNF was influenced by the size of clones scored and the source of colony-stimulating activity. The response of L-CFC to recombinant IFN-alpha and/or -gamma was highly variable, and sensitivity to one of the lymphokines did not predict for sensitivity to another. The response of L-CFC to combinations of rTNF- alpha and either IFN-alpha or IFN-gamma was complex, varying from synergistic to additive and indifferent. In three of six specimens, IFN- gamma acted antagonistically with rTNF-alpha, a phenomenon not observed with IFN-alpha. These observations suggest that the action of rTNF- alpha in acute myelogenous leukemia could be exploited therapeutically and the dose-time-response relationship should be considered in designing treatment schedules.(ABSTRACT TRUNCATED AT 400 WORDS)

Activated Endothelial Cells Induce Apoptosis in Leukemic Cells by Endothelial Interleukin-8

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2672-2680 ◽  
Author(s):  
Yasuhito Terui ◽  
Masayuki Ikeda ◽  
Hiroshi Tomizuka ◽  
Tadashi Kasahara ◽  
Tetsuya Ohtsuki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Cell Lines ◽  
Tumor Necrosis ◽  
K562 Cells ◽  
Interleukin 8 ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Necrosis Factor ◽  
Stimulation Of

Tumor cells are eradicated by several systems, including Fas ligand-Fas and tumor necrosis factor (TNF)-tumor necrosis factor receptor (TNFR). In the previous study, we purified an apoptosis-inducing factor (AIF) to homogeneity from a medium conditioned by PDBu-treated HL-60 cells. N-terminal sequence analysis showed that AIF is identical to endothelial interleukin-8 (IL-8). A novel apoptosis system, in which endothelial cells participate via endothelial IL-8 release, is identified here. Human umbilical vein cells (VE cells) produce and secrete IL-8 by stimulation of IL-1 and TNF-. Endothelial IL-8, which is secreted from VE cells by stimulation of IL-1 and TNF- , induces apoptosis in myelogenous leukemia cell line K562 cells. Monocyte-derived IL-8 could not induce apoptosis in K562 cells. Moreover, interaction between VE cells and K562 cells induces the release of endothelial IL-8 from VE cells, and the attached K562 cells undergo apoptosis. Moreover, interactions between VE cell and other cell lines, such as HL-60, U937, Jurkat, and Daudi, induce the secretion of endothelial IL-8 and the induction of apoptosis in cell lines. Endothelial IL-8 significantly inhibits tumor growth of intraperitoneal and subcutaneous tumor mass of K562 cells and induces apoptosis in their cells in vivo. Endothelial IL-8 plays an important role in apoptosis involving endothelial cells, which may provide us with a new therapy for hematological malignancies. © 1998 by The American Society of Hematology.

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