Hematologic Manifestations of Deficiency of Adenosine Deaminase 2 (DADA2) and Response to Tumor Necrosis Factor Inhibition in DADA2-Associated Bone Marrow Failure

2018 ◽  
Vol 38 (2) ◽  
pp. 166-173 ◽  
Author(s):  
Thomas F. Michniacki ◽  
Mark Hannibal ◽  
Charles W. Ross ◽  
David G. Frame ◽  
Adam S. DuVall ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Necrosis Factor ◽  
Adenosine Deaminase ◽  
Tumor Necrosis ◽  
Bone Marrow Failure ◽  
Tumor Necrosis Factor Inhibition ◽  
Adenosine Deaminase 2 ◽  
Necrosis Factor

Tumor Necrosis Factor-Mediated Inflammation Exacerbates Genomic Instability and Promotes Leukemia Development.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4265-4265
Author(s):  
June Li ◽  
Daniel P. Sejas ◽  
Xiaoling Zhang ◽  
Reena Rani ◽  
Qishen Pang
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Tumor Necrosis Factor ◽  
Genomic Instability ◽  
Tumor Necrosis ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Leukemic Transformation ◽  
Leukemia Development ◽  
Necrosis Factor

Abstract A correlation has been shown between elevated circulating pro-inflammatory cytokines and anemia in patients with leukemia-related diseases but direct evidence for the mechanistic link between inflammation and leukemia is lacking. We have investigated the role of the pro-inflammatory cytokine tumor necrosis factor a (TNF-a) in leukemic development using the disease model of Fanconi anemia, a genetic disorder clinically characterized by congenital anomalies, progressive bone marrow failure, and a high risk of developing leukemia and other cancers. We demonstrate that long-term TNF-a exposure of Fanconi bone marrow progenitors enhances inflammatory response, promotes clonal proliferation, and ultimately leads to leukemia development. NF-kB activation is required for TNF-a-promoted progenitor growth and early stage of leukemia development but is dispensable for the maintenance of leukemic transformation. Pharmacological elimination of TNF-a-induced reactive oxygen species reduces inflammation and delays leukemia development, suggesting that oxidative damage may serve as a link between inflammation and leukemia. In addition, TNF-a-promoted leukemic cells show persistent DNA damage response and increased genomic instability. Furthermore, correction of Fanconi genetic deficiency prevents clonal progenitor proliferation and leukemic transformation by eliminating oxidative DNA damage. Thus, inflammation can exacerbate genomic instability and contribute to leukemia development. This may explain, at least in part, why cells with genomic instability have high predisposition to cancer. Our study underscores therapeutic value of anti-oxidants and anti-inflammation towards tumorigenesis.

scholarly journals Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk

2015 ◽  
Vol 31 (3) ◽  
pp. 557-574 ◽  
Author(s):  
Hervé Lebrec ◽  
Rafael Ponce ◽  
Bradley D. Preston ◽  
Jan Iles ◽  
Teresa L. Born ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Cancer Risk ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Inhibition ◽  
Necrosis Factor

scholarly journals Tumor Necrosis Factor α Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl–Rank Interaction

2000 ◽  
Vol 191 (2) ◽  
pp. 275-286 ◽  
Author(s):  
Kanichiro Kobayashi ◽  
Naoyuki Takahashi ◽  
Eijiro Jimi ◽  
Nobuyuki Udagawa ◽  
Masamichi Takami ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Fab Fragment ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Osteoclast differentiation factor (ODF, also called RANKL/TRANCE/OPGL) stimulates the differentiation of osteoclast progenitors of the monocyte/macrophage lineage into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF, also called CSF-1). When mouse bone marrow cells were cultured with M-CSF, M-CSF–dependent bone marrow macrophages (M-BMMφ) appeared within 3 d. Tartrate-resistant acid phosphatase–positive osteoclasts were also formed when M-BMMφ were further cultured for 3 d with mouse tumor necrosis factor α (TNF-α) in the presence of M-CSF. Osteoclast formation induced by TNF-α was inhibited by the addition of respective antibodies against TNF receptor 1 (TNFR1) or TNFR2, but not by osteoclastogenesis inhibitory factor (OCIF, also called OPG, a decoy receptor of ODF/RANKL), nor the Fab fragment of anti–RANK (ODF/RANKL receptor) antibody. Experiments using M-BMMφ prepared from TNFR1- or TNFR2-deficient mice showed that both TNFR1- and TNFR2-induced signals were important for osteoclast formation induced by TNF-α. Osteoclasts induced by TNF-α formed resorption pits on dentine slices only in the presence of IL-1α. These results demonstrate that TNF-α stimulates osteoclast differentiation in the presence of M-CSF through a mechanism independent of the ODF/RANKL–RANK system. TNF-α together with IL-1α may play an important role in bone resorption of inflammatory bone diseases.

scholarly journals Gamma-interferon and tumor necrosis factor production after bone marrow transplantation is augmented by exposure to marrow fibroblasts infected with cytomegalovirus

Blood ◽  
1990 ◽  
Vol 76 (5) ◽  
pp. 1046-1053 ◽  
Author(s):  
AS Duncombe ◽  
A Meager ◽  
HG Prentice ◽  
JE Grundy ◽  
HE Heslop ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Tumor Necrosis Factor ◽  
Marrow Transplantation ◽  
Tumor Necrosis ◽  
Gamma Interferon ◽  
Cmv Infection ◽  
Necrosis Factor

Abstract After bone marrow transplantation (BMT), mortality from viral infections such as cytomegalovirus (CMV) remains high. Gamma-Interferon (gamma IFN) and tumor necrosis factor (TNF) are produced constitutively after BMT and have anti-viral properties. To study the effects of these cytokines on CMV interaction with host cells, we have used patient marrow fibroblasts since marrow stroma is a target for CMV infection correlating with myelosuppression in vivo. Both gamma IFN and TNF are constitutively produced by recipient CD3+ and CD16+ lymphocytes, but not by their marrow fibroblasts. Secretion by peripheral blood mononuclear cells is increased if they are cultured with host fibroblasts infected with CMV in vitro and the levels of gamma IFN and TNF produced are within the range that protects fresh fibroblasts from CMV infection. Constitutive secretion of cytokines by lymphocytes declines by 8 weeks after BMT, a time when the risk of CMV disease increases sharply. The in vitro phenomenon that we have described needs to be evaluated in correlative studies on individual BMT recipients to determine whether such a cytokine-mediated defense mechanism against CMV may operate in vivo.

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