Tumor necrosis factor‐α overproduction in Fanconi's anemia

Schultz, Jo El J.; Shahidi, Nasrollah T.

doi:10.1002/ajh.2830420211

Cited by 91 publications

(68 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FA patients are hypersensitive to and have elevated levels of TNF␣, which promotes clonal evolution and leukemogenesis. [22][23][24][25] The combination of genetic instability and cytokine hypersensitivity creates an environment that supports the selection of leukemic over nonleukemic stem cells. 26,27 Malignant clones that arise are not only TNF␣-resistant, but give rise to progeny that over-produce TNF␣, further augmenting the selective pressure for expansion of the malignant clone over the hypersensitive parental stem cell pool.…”

Section: Discussionmentioning

confidence: 99%

TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

Fleischman

Aichberger

Luty

et al. 2011

Blood

247

240

View full text Add to dashboard Cite

IntroductionMany cases of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are characterized by an activating point mutation of JAK2 (JAK2 V617F ). It has been generally accepted that JAK2 V617F -positive cells outpace normal hematopoietic cells as a result of constitutively active growth factor signaling 1 ; however, failure of JAK2 V617F to confer a significant competitive advantage over normal hematopoiesis in 2 independent knock-in MPN models 2,3 suggests that additional factors may be required to promote expansion of JAK2 V617F -positive cells in patients.As MPN patients overproduce certain proinflammatory cytokines known to suppress normal hematopoiesis, 4 it is conceivable that JAK2 V617F may protect mutant stem cells and progenitors from the apoptotic cues induced by these cytokines.In this context, we recently observed that TNF␣ levels are elevated in mice with retrovirally induced JAK2 V617F MPN. 5 The physiologic effects of TNF␣ are complex and cell type-dependent, ranging from stimulation of proliferation to induction of apoptosis. 6 TNF␣ negatively regulates the expansion and self-renewal of pluripotent hematopoietic stem cells (HSCs) 7,8 and has inhibitory effects on normal as well as some leukemic human hematopoietic progenitor cells. [9][10][11] TNF␣'s involvement in the evolution of leukemia is not without precedent. Studies in Fanconi anemia (FA) have implicated TNF␣ hypersensitivity as a central mechanism of clonal evolution and progression to acute myeloid leukemia. In the FA Complementation Group C murine model (Fancc Ϫ/Ϫ ) TNF␣ induces bone marrow failure 12 and can promote the evolution of somatically mutated TNF␣-resistant preleukemic stem cell clones. 13 Taking into account TNF␣'s role in clonal evolution and that elevated TNF␣ levels are present in human MPN we hypothesized that JAK2 V617F induces TNF␣ expression and simultaneously confers TNF␣ resistance to MPN progenitor cells. Methods Isolation and culture of primary cellsBlood mononuclear cells (MNCs) were obtained from peripheral blood samples of patients with polycythemia vera (PV) and essential thromobocythemia (ET), myelofibrosis (MF), or normal volunteers. CD34 ϩ cells were obtained from bone marrow of normal, PV and ET patients or peripheral blood of MF patients. All patients gave their informed consent in accordance with the Declaration of Helsinki to participate in the study, which was approved by the Institutional Review Boards of Oregon Health & Science University (OHSU), Portland Veterans Affairs Medical Center, Cornell University, and Freiburg University.Submitted April 13, 2011; accepted August 7, 2011. Prepublished online as Blood First Edition paper, August 22, 2011; DOI 10.1182 DOI 10. /blood-2011 An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''adverti...

show abstract

Section: Discussionmentioning

confidence: 99%

TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

Fleischman

Aichberger

Luty

et al. 2011

Blood

247

240

View full text Add to dashboard Cite

show abstract

“…8,9 For example, levels of proapoptotic cytokines tumor necrosis factor-␣ (TNF-␣) and interferon-␥ (IFN-␥) are elevated in FA lymphocytes, bone marrow cells, and FA patient serum samples. [10][11][12] FA bone marrow cells (at least of the C complementation group) are also hypersensitive to these cytokines and undergo apoptosis when exposed to even low levels of them. [13][14][15] To better understand FA, multiple murine knockout models, including Fanca Ϫ/Ϫ , Fancc Ϫ/Ϫ , Fancg Ϫ/Ϫ , Fancd2 Ϫ/Ϫ , Fanca Ϫ/Ϫ -Fancc Ϫ/Ϫ double, and Fancl Ϫ/Ϫ mice, have been developed.…”

Section: Fancd1/brca2 Fancd2 Fance Fancf Fancg/xrcc9 Fanci Fancmentioning

confidence: 99%

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

Zhang

Marquez-Loza

Eaton

et al. 2010

Blood

106

View full text Add to dashboard Cite

Progressive bone marrow failure is a major cause of morbidity and mortality in human Fanconi Anemia patients. In an effort to develop a Fanconi Anemia murine model to study bone marrow failure, we found that Fancd2 ؊/؊ mice have readily measurable hematopoietic defects. Fancd2 deficiency was associated with a significant decline in the size of the c-Kit ؉ Sca-1 ؉ Lineage ؊ (KSL) pool and reduced stem cell repopulation and spleen colony-forming capacity. Fancd2 ؊/؊ KSL cells showed an abnormal cell cycle status and loss of quiescence. In addition, the supportive function of the marrow microenvironment was compromised in Fancd2 ؊/؊ mice. Treatment with Sirt1-mimetic and the antioxidant drug, resveratrol, maintained Fancd2 ؊/؊ KSL cells in quiescence, improved the marrow microenvironment, partially corrected the abnormal cell cycle status, and significantly improved the spleen colony-forming capacity of Fancd2 ؊/؊ bone marrow cells. We conclude that Fancd2 ؊/؊ mice have readily quantifiable hematopoietic defects, and that this model is well suited for pharmacologic screening studies. IntroductionFanconi anemia (FA) is a rare, autosomal, recessive genetic disorder associated with severe birth defects, cancer predisposition, and bone marrow failure. Thirteen causative genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCL/PHF9/Pog, FANCJ/BRIP1/BACH1, FANCM/Hef, and FANCN/ PALB2) have been identified and cloned to date, and the encoded proteins are believed to work together in a common DNA damageresponse pathway to maintain genomic integrity and protect the genome from DNA damage induced by cross-linking agents. 1,2 Although deficiency in DNA cross-link repair renders all FA cells susceptible to cross-linking agents, bone marrow is the most affected organ system. Mutations in any of the different FA genes almost universally lead to bone marrow failure, which is the primary cause of mortality in FA. 3 The pathogenesis of bone marrow failure in FA remains elusive. Mutations in several genes involved in DNA damage repair, including Atr, XPD, and Ercc1, caused either hematopoietic stem cell (HSC) loss or impaired HSC function under conditions of stress. [4][5][6] These studies suggest that the maintenance of genome integrity is critical for HSC survival and function. However, the extent to which genotoxicity, resulting from impaired DNA damage repair, contributes to bone marrow failure in FA is unclear. 7 Other pathways associated with hematopoietic failure, such as altered cytokine signaling, may also contribute to FA pathogenesis. 8,9 For example, levels of proapoptotic cytokines tumor necrosis factor-␣ (TNF-␣) and interferon-␥ (IFN-␥) are elevated in FA lymphocytes, bone marrow cells, and FA patient serum samples. 10-12 FA bone marrow cells (at least of the C complementation group) are also hypersensitive to these cytokines and undergo apoptosis when exposed to even low levels of them. [13][14][15] To better understand FA, multiple murine knockout models, includingand Fancl Ϫ/Ϫ m...

show abstract

“…A consistent body of evidence has been accumulated since then, both related to phenotypic redox abnormalities and related to the involvement of FA proteins in redox pathways (Ahmad et al 2002;Bogliolo et al 2002;Pagano et al 1998;Pagano and Korkina 2000;Pagano and Youssoufian 2003), as summarized in Table 4. FA cells are characterized by a) excess oxidative DNA damage ] in hydrogen peroxide-exposed FA cells (Takeuchi and Morimoto 1993), and in freshly drawn white blood cells from FA patients (Degan et al 1995); b) increased oxygen sensitivity (Joenje et al 1981) and sensitivity to free iron (Poot et al 1996); c) correction of chromosomal abnormalities by either antioxidant enzymes or by low-molecularweight antioxidants (Dallapiccola et al 1985;Nordenson 1977;Raj and Heddle 1980); d) excess plasma levels of clastogenic factor (Emerit et al 1995) and of tumor necrosis factor-α (TNF-α; Dufour et al 2003;Schulz and Shahidi 1993); e) involvement of redoxactive cytokines, such as TNF-α and interferon-γ (Dufour et al 2003;Pearl-Yafe et al 2003), and of inducible nitric oxide synthase (Hadjur and Jirik 2003); and d) an involvement of Trx, which corrects MMC and DEB sensitivity in FA cells (Ruppitsch et al 1998) and occurs in lower-than-normal levels in FA fibroblasts (Kontou et al 2002). Together, a well-established body of evidence on FA cellular phenotype, along with the roles for some FA proteins in redox pathways (Bogliolo et al 2002;Pagano and Youssoufian 2003), combine to support a central role for oxidative stress both in FA cellular phenotype and in FA protein functions.…”

Section: Prooxidant State In Fa Phenotypementioning

confidence: 99%

Oxidative stress-related mechanisms are associated with xenobiotics exerting excess toxicity to Fanconi anemia cells.

Pagano¹,

Manini²,

Bagchi³

2003

Environ Health Perspect

View full text Add to dashboard Cite

Tumor necrosis factor‐α overproduction in Fanconi's anemia

Cited by 91 publications

References 42 publications

TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

Oxidative stress-related mechanisms are associated with xenobiotics exerting excess toxicity to Fanconi anemia cells.

Contact Info

Product

Resources

About