As a novel cancer-testis antigen, sperm‑associated antigen 6 (SPAG6) has been reported to regulate apoptosis through the tumor necrosis factor-related apoptosis-inducing ligand signaling pathway in the MDS cell line SKM‑1.
In a French multicenter retrospective study, we analyzed the efficacy and safety of biologics (tumor necrosis factor-α [TNF-α] antagonists, tocilizumab, rituximab and anakinra) for SIADs associated with myelodysplastic syndromes (MDSs).
Our results demonstrate that TNF and IL6 gene polymorphisms, as underlying host features, are likely to play a key role in influencing the severity of the cytopenias in MDS and they may be instrumental for tailoring cytokine-target therapies.
These findings suggest that S100A9 and its nuclear factor-κB transcriptional target, tumor necrosis factor-α, directly suppress erythropoietin elaboration in myelodysplastic syndromes.
Particularly, strong over-expression of BIK (BCL2-interacting killer) was observed in erythroid progenitor cells of low- and high-risk MDS patients (both p = 0.001) and TNFRSF4 (tumor necrosis factor receptor superfamily 4) was down-regulated in immature hematopoietic cells (p = 0.0023) of low-risk MDS patients compared to healthy bone marrow.
In stratified analysis by disease type, there was a significant association between the TNF-α -308 G>A polymorphism and increased risk of aplastic anemia but no significant association with myelodysplastic syndrome (AA vs. GG: OR=2.23, 95% CI=1.23-4.05, P=0.006; recessive model: OR=3.52, 95% CI=1.30-9.53, P=0.010).
Among them, SCF and SDF-1 may play roles in the apoptosis of HSCs in MDS; and IFN-γ, TNF-α, and B7-H1 may be associated with apoptosis of bone marrow cells in MDS.
The production of IFN-γ and TNF-α by CD4(+) and CD8(+) T lymphocytes from patients with lower-risk MDS could be enhanced by recombinant human IL-17 (rhIL-17) treatment.
Our data demonstrated that L-MDS cohort had increased frequencies of peripheral Th22 cells and higher mRNA expression levels of IL-6 and TNF-α, indicating that Th22 cells along with Th17 cells or not are involved in the dynamic immune responses of MDS.
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.
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.
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.
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.
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.
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.
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.