Review
TNF-α signaling in Fanconi anemia

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Abstract

Tumor necrosis factor-alpha (TNF-α) is a major pro-inflammatory cytokine involved in systemic inflammation and the acute phase reaction. Dysregulation of TNF production has been implicated in a variety of human diseases including Fanconi anemia (FA). FA is a genomic instability syndrome characterized by progressive bone marrow failure and cancer susceptibility. The patients with FA are often found overproducing TNF-α, which may directly affect hematopoietic stem cell (HSC) function by impairing HSC survival, homing and proliferation, or indirectly change the bone marrow microenvironment critical for HSC homeostasis and function, therefore contributing to disease progression in FA. In this brief review, we discuss the link between TNF-α signaling and FA pathway with emphasis on the implication of inflammation in the pathophysiology and abnormal hematopoiesis in FA.

Introduction

Fanconi anemia (FA) is a rare inherited disease associated with bone marrow failure (BMF), variable congenital/developmental abnormalities, and cancer susceptibility [1], [2], [3]. Approximately 1000 persons worldwide currently suffer from the disease, 10 to 20 children are born with FA in the United States each year [1]. It is genetically heterogeneous, with 16 complementation groups identified thus far [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]. The genes encoding the groups A (FANCA), B (FANCB), C (FANCC), D1 (FANCD1/BRCA2), D2 (FANCD2), E (FANCE), F (FANCF), G (FANCG), I (FANCI/KIAA1794), J (FANCJ/BRIP1), L (FANCL), M (FANCM), N (FANCN/PALB2), O (FANCO/RAD51C), P (FANCP/SLX4) and Q (FANCQ/ERCC4/XPF) proteins have been cloned ([4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], Table 1), of which FANCA, FANCG and FANCC are the most commonly mutated genes in FA populations ([2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], Fig. 1). At the cellular level, FA is characterized by chromosomal instability and cross-linker sensitivity, which serves as a clinical diagnostic hallmark of FA [1], [3]. Strong evidence indicates that the products of all of the FA genes function together in the FA pathway. In fact, the prominent role of the FA pathway has been implicated in DNA damage response and/or repair (DDR) [27].

Section snippets

Multifunctionality of FA proteins

Intense studies have been focusing on biological function of FA proteins. Compelling evidence suggested that eight of the FA proteins (namely, FANCA, B, C, E, F, G, L, and M) and 6 associated factors (FAAP100, FAAP24, FAAP20, HES1, MHF1 and MHF2) form a nuclear multiprotein complex, which is required for the efficient mono-ubiquitination of downstream FANCD2/FANCI dimer in response to DNA damage or DNA replication stress [2], [8], [9], [12], [18], [28], [29], [30], [31], [32], [33], [34], [35],

Hematopoietic failure and abnormal apoptotic signaling in FA

The most common clinical features of FA are hematological. A majority of children with FA invariably experience pancytopenia during the first few years of life, which is associated with stem cell loss in the hematopoietic compartment. Complications of bone marrow failure (BMF) are the major causes of morbidity and mortality of FA [1], [44], [45], [46], [47], [48]. In addition, rapid hematopoietic cell loss forces compensatory chronic proliferation, which may lead to leukemogenesis [14], [49],

The link between pro-inflammatory cytokine TNF-α, inflammation and diseases

TNF-α is a proinflammatory cytokine produced by multiple immune and non-immune cells, including lymphocytes, mast cells, endothelial cells, fibroblasts and adipocytes. It functions in the regulation of diverse physiological cellular events, including cell proliferation, differentiation and apoptosis as well as various inflammatory processes [93], [94]. TNF-α is also involved in pathological actions, such as systematic inflammation and initiation of the acute phase reaction by promoting

TNF-α signaling in pathophysiology

The molecular mechanisms of TNF-α functions have been intensively investigated. It is believed that the biological activities of TNF-α are mediated by two structurally related but functionally distinct receptors, designated as the p55 and p75 TNF-α receptors, TNFR1 and TNFR2, respectively [93]. Binding of TNF-α to the receptors initiates a complex array of signaling events in response to TNF-α receptor activation and gives rise to the pleiotropic effects of TNF-α on cells [107], [108], mainly

The roles of TNF-α in HSC function and leukemic transformation in general

HSC function is regulated by microenvironment directly through cell–cell interactions or indirectly through production of cytokines [155]. Many cytokines and growth factors including TNF-α are known to regulate HSC survival, homing, and proliferation [156]. TNF-α plays a pivotal role in directly regulating HSC proliferation or indirectly stimulating growth factor production and up-regulation of cytokine receptors. While TNF-α induces proliferation of the more primitive subset of progenitors, it

The roles of TNF-α in HSC function and leukemic transformation in FA

Elevated levels of serum, plasma or intracellular TNF-α are often found in patients with FA. The increased secretion of TNF-α along with altered production of other growth factors and cytokines, including reduced expression of interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor, may change the BM microenvironment by leading to factor deprivation or constant exposure to mitogenic inhibitors [26]. These expression alterations may cause deregulation of cellular homeostasis

Therapies targeting inflammatory cytokines in treatment of human diseases including hematologic diseases

Cytokines are a large family of small proteins that function in essentially all biological processes. Abnormalities in cytokine expression, their receptors, and the signaling pathways are involved in variety of diseases, such as immune and inflammatory disorders and cancers [93]. As cytokines are potent rate-limiting extracellular molecules, therapies targeting cytokines by greater surface of interaction of receptors and antibodies with their targets have gained variable successes. For example,

Summary

The pro-inflammatory cytokine, TNF-α has been considered as one important pathological factor involved in the abnormal hematopoiesis most commonly found in BMF diseases including FA, an excellent disease model for studying BMF and leukemogenesis. Although the molecular pathogenesis of FA remains to be elucidated, overproduction of TNF-α in FA most likely plays a dual role. It may act as both a death mediator and a leukemic promoter. Understanding the relationship between inflammation and FA

Conflict of interest

The authors declare no conflict of interest.

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      The designation of FA as a DNA repair disorder, and the recent literature cited above, leads naturally to the inclination to interpret all pathologies as the result of this deficiency. However, the groups of Grover Bagby and Qishen Pang, among others, have argued that the BMF observed in FA children is a consequence of multiple adverse effects provoked by the pro-inflammatory state of FA patients (Bagby, 2003; Du et al., 2014). This view is extended in recent work in which it was shown that DNA damage and repair deficiencies do not explain the over-production of inflammatory cytokines by FA cells (Garbati et al., 2015).

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    The authors are supported by NIH grants R01 HL076712 and R01 CA157537. Q.P. is supported by a Leukemia and Lymphoma Scholar award. W.D. is supported by a NIH T32 grant.

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