Fanconi Anemia

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Fanconi anemia (FA) is an autosomal and X-linked recessive disorder characterized by bone marrow failure, acute myelogenous leukemia, solid tumors, and developmental abnormalities. Recent years have seen a dramatic improvement in FA patient treatment, resulting in a greater survival of children into adulthood. These improvements have been made despite the fact that a definitive cellular function for the proteins in the FA pathway has yet to be elucidated. Delineating the cellular functions of the FA pathway could help further improve the treatment options for FA patients and further reduce the probability of succumbing to the disease. This article reviews the current clinical aspects of FA including presentation, diagnosis, and treatment followed by a review of the molecular aspects of FA as they are currently understood.

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Clinical aspects of Fanconi anemia

In earlier times, children with FA had the inevitable outcome of death, because most FA patients present with aplastic anemia and little in the way of supportive care was available. In the first part of the twentieth century, the advent of modern blood banking allowed the clinician to stem the immediacy of anemia and thrombocytopenia that resulted in death. As a result, the next major issue for these children became infection, even with the development of antibiotics. Neutropenic infections are

Presentation

Even though a classic set of features generally characterize these patients, FA children typically present in the first decade of life on recognition of aplastic anemia.1, 2, 3 Nonetheless, classic features of FA consist of thumb and radial absence, malformation, or even less obvious features, such as a deeper cleft between the first two digits. In much the same way as the facial features of children affected by Down's syndrome allow easy recognition of their affliction, children with FA

Diagnosis

Once it is recognized that a patient has a production defect resulting in the occurrence of more than one cell line abnormally low, it is incumbent on the clinician to then proceed to an examination of the bone marrow. At the time of the bone marrow procedure, it is critical not only to perform aspiration but also a biopsy so that cellularity may be assessed and pathologic examination for evidence of leukemia undertaken. Aspirate samples are sent typically for flow cytometry to rule out further

Acute myelogenous leukemia

Even though 90% of FA patients first present with bone marrow failure, a certain percentage nonetheless display AML as the first evidence of FA. These cases of AML are typically M1-M4 FAB subtype and display no characteristic cytogenetic or molecular abnormality, although numerous translocations, deletions, and other aneuploidogenic changes can be found.14, 15 The most ominous part of a diagnosis of AML is the fact that FA patients cannot be treated in a typical fashion as other AML patients,

Stem cell transplantation

The decision to go forward with SCT in an FA patient is one not to be taken lightly. Under the best of circumstances in a patient unafflicted by FA, going forward electively with SCT presents risks and potential for morbidity. Total body irradiation and cyclophosphamide, which are typical parts of conditioning regimens, can result in long-term effects on growth, cognition, and secondary malignancy. In addition, the potential of graft-versus-host disease can result in long-term complications

Molecular aspects of Fanconi anemia

At the molecular level, cells derived from FA patients display hypersensitivity to DNA cross-linking agents, such as MMC and diepoxybutane. Treatment with these agents induces an abnormally prolonged cell cycle arrest in S phase and an accumulation of cells with 4 N DNA.41 As the result of this response, the FA pathway has been hypothesized to function in sensing DNA damage induced by these agents and in initiating its repair. This hypothesis has been supported by work elucidating the

Fanconi anemia core complex proteins

The nuclear “core” complex is composed of 8 of the 13 FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM). This core complex is required for the monoubiquitylation of FANCD2 and FANCI.42 Although the reason for the necessity of an intact FA core complex for these modifications is not well understood, biallelic mutation or deletion of any one of the genes that encode these eight core proteins results in failure to monoubiquitylate FANCD2 and FANCI. The exact mechanism by

FANCD2-FANCI

Following treatment with DNA cross-linking agents59 or during S phase of the cell cycle,60 FANCD2 and FANCI become monoubiquitylated. These modifications result in the translocation of the two proteins to chromatin within cells where they colocalize with DNA repair proteins including the downstream effector FA proteins at sites of DNA damage.61, 62, 63 An intact core complex is necessary for the monoubiquitylation of FANCD2 on lysine 56161 and FANCI on lysine 523.62, 63 FANCI is a relatively

The “downstream” proteins: FANCD1, FANCJ, and FANCN

The FANCD1 gene is identical to the familial breast-ovarian cancer susceptibility gene BRCA2 and as such, biallelic mutation of the FANCD1/BRCA2 gene results in the FA-D1 subtype of FA, whereas monoallelic mutation results in increased breast and ovarian cancer susceptibility.68 The main contribution of the FANCD1 protein to the FA pathway is through its ability to recruit Rad51 into the DNA damage-inducible nuclear foci, which FANCD2 translocates into following monoubiquitylation.69 Rad51 is a

The Fanconi anemia pathway and DNA repair

Cells derived from FA patients display hypersensitivity to DNA cross-linking agents, such as MMC and diepoxybutane.59 Treatment of cells derived from FA patients with DNA cross-linking drugs has been shown to induce an abnormally prolonged cell cycle arrest in S phase and an accumulation of cells containing 4 N DNA.41 The mechanism by which the interstrand and intrastrand cross-links induced by these drugs are resolved in mammals is not well understood. Although it is known that nucleotide

The Fanconi anemia pathway and homologous recombination proteins

One of the most obvious connections between the FA and HR pathways is the interaction between FANCD1/BRCA2 and RAD51. RAD51 is the mammalian homolog of the bacterial RecA protein, which is a ssDNA binding protein necessary for catalyzing the strand invasion step of HR.84 The interaction between BRCA2 and RAD51 was first discovered through a yeast two-hybrid screen.85 The importance of this interaction to the FA pathway was not understood until the gene mutated in FA-D1 patients was discovered

The Fanconi anemia pathway and translesion synthesis proteins

To continue replicating through sites of DNA damage, which block replicative polymerases and lead to replication fork stalling, cells use TLS polymerases. Each TLS polymerase is specialized to replicate through a specific type of DNA lesion and keep the replication fork moving regardless of DNA damage.96 The protein proliferating cell nuclear antigen (PCNA) plays an essential role in this switch from replicative to TLS polymerase. PCNA functions as a polymerase clamp, tethering a polymerase to

The Fanconi anemia pathway and cell signaling

The FA pathway also interacts with the DNA damage response through the DNA sensing and signaling proteins ataxia telangiectasia and ATM kinase, ATM and ATR kinase, and Chk1 kinase. Cells from patients with ataxia telangiectasia display radiohypersensitivity, cell cycle checkpoint defects, and chromosomal instability. The ATM protein is a serine-threonine kinase and is a member of the phosphatidylinositol-3 kinase–related protein kinase family of kinases. The main function of ATM seems to be

The Fanconi anemia pathway, oxidative stress, cytokine sensitivity

Teleologically, the involvement of very specific developmental abnormalities in FA patients implies that the FA proteins have the potential for other functions aside from those they perform in protecting the genome. Others have argued that the main function of the FA pathway is to regulate oxidative stress, because reactive oxygen species have been documented to be involved in bone marrow failure,116, 117 cancer,118 endocrinopathies,119 abnormalities in skin pigmentation,120 and malformations.

Summary

Knowledge about the pathway and the disease seems to grow exponentially with each passing year, because two of the FA proteins (FANCI and FANCN) were discovered and characterized in 2007. The body of work has delineated a pathway with three distinct subdivisions of proteins, but many questions remain to be answered. Some questions involve the function of individual FA proteins: Is FANCL the E3 ubiquitin ligase for FANCD2 and FANCI? Is the helicase activity of FANCM important to the FA pathway

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