This paper reports on the production of tumor necrosis factor (TNF) and granulocyte macrophage colony-stimulating factor (GM-CSF) by cultured mononuclear adherent cells derived from bone marrow of 25 patients affected by myelodysplastic syndrome (MDS) of different FAB subtypes.
These results suggested that disruption of hematopoiesis in MDS might be caused by enhanced production of inhibitory regulatory cytokines especially TNF-alpha and occasionally IFN-gamma by bone marrow macrophages.
Using our newly developed in situ double-labeling technique that sequentially employs DNA polymerase (DNA Pol) followed by terminal deoxynucleotidyl transferase (TdT) to label cells undergoing apoptosis, we have characterized DNA fragmentation patterns during spontaneous apoptosis in MDS bone marrow and in HL60 cells treated with TNF-alpha or etoposide (VP16).
Rates of proliferation and apoptosis as well as expression of tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta) and the number of macrophages were measured in bone marrow (BM) biopsies of 33 patients who presented with hypocellular (cellularity < 30%) myelodysplastic syndromes (MDS).
We conclude that a spontaneous and rapid down-regulation of Fap-1, possibly induced by TNF-alpha, a cytokine shown to be present in excess in MDS marrows, may underlie the increased apoptotic death of hematopoietic cells in these patients.
In previously diagnosed group, Flt-3 rec (p = 0.001), TNF-alpha (p = 0.04) and IL-1 beta (p = 0.016) were higher than normal while there was no statistically significant difference in the newly versus previously diagnosed MDS cases:
Here we analyzed marrow samples from 80 patients with MDS in regard to TNF-alpha and Fas-ligand levels and a possible correlation with various disease parameters and risk factors.
Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and its receptors in myelodysplastic syndrome: effects on in vitro hemopoiesis.
We can find no genetic influence for these polymorphisms in HLA class I/II, TNF-alpha/LT-alpha and IL-10 loci on either predisposition or disease progression in MDS/AML.
The constitutive expression of mRNA for TNF receptors (TNFR), including TNFRI and TNFRII, and the adapter molecules, such as the TNF receptor-associated death domain protein (TRADD), Fas-associated death domain protein (FADD), receptor interacting protein (RIP) and TNF receptor-associated factor 2 (TRAF-2) were analyzed by reverse transcriptase (RT)-PCR in bone marrow samples from control, MDS and AML cases.
The objective of this study was to investigate the association between TNF-alpha and TGF-beta1 gene polymorphisms and the susceptibility to MDS and the progression of the disease among patients with MDS belonging to the refractory anemia (RA) subtype.
As TNF overproduction has been implicated in the pathophysiology of bone marrow failure states, we determined whether pharmacologic inhibition of p38 reverses the hematopoietic defects seen in bone marrows from patients with myelodysplastic syndromes (MDS) and the anemia of chronic disease.
Polymorphisms associated with increased expression in the cytokines TNFalpha and TGFbeta1 are overrepresented in the MDS population suggesting that increased TNF-alpha and TGF-beta1 activity may contribute to the susceptibility and/or pathogenesis of MDS.
Polymorphisms associated with increased expression in the cytokines TNFalpha and TGFbeta1 are overrepresented in the MDS population suggesting that increased TNF-alpha and TGF-beta1 activity may contribute to the susceptibility and/or pathogenesis of MDS.
Changes in peripheral blood are reflected in alterations in cell kinetics, transferrin receptor expression and markedly increased apoptosis and cell death in the bone marrow indicating that TNF-alpha may contribute to myelodysplasia in ACD.
Further, inhibition of nuclear factor-kappaB (NF-kappaB) activation in TNF-alpha-treated cells resulted in profound apoptosis in FLIPS, but not in FLIPL-overexpressing cells, consistent with the observations in patients with early stage MDS.
We have shown that marrow stroma-derived signals convey sensitivity to tumor-necrosis-factor alpha (TNF-alpha)-mediated apoptosis in otherwise-resistant KG1a myeloid cells and CD34(+) cells from MDS marrow.
However, there was a significant correlation between DR15 and TNF polymorphisms at position -308 among patients with MDS, and the TNF-308 AG genotype conferred an increased risk of NRM compared with the GG genotype (hazard ratio [HR], 1.49; P = .02), even after adjusting for DR15.
Coculture with HS5 stroma resulted in down-regulation of TWIST and increased apoptosis in response to TNFα in CD34(+) cells from advanced MDS; the same effect was achieved by TWIST-specific RNA interference in CD34(+) cells.
Also, an overexpression of TNFα may promote an underlying proinflammatory state that cooperates with intrinsic defects within MDS progenitors to increase the severity of certain phenotypic features of the disease.
Our systematic model revealed that the dynamic response patterns of p38 MAPK and JNK to TNF-α stimulation in MDS were different from that observed in normal marrow cells.