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Dysregulated Ca2+ homeostasis in Fanconi anemia cells.

ABSTRACT: Fanconi Anemia (FA) is a rare and complex inherited blood disorder associated with bone marrow failure and malignancies. Many alterations in FA physiology appear linked to red-ox unbalance including alterations in the morphology and structure of nuclei, intermediate filaments and mitochondria, defective respiration, reduced ATP production and altered ATP/AMP ratio. These defects are consistently associated with impaired oxygen metabolism indeed treatment with antioxidants N-acetylcysteine (NAC) and resveratrol (RV) does rescue FA physiology. Due to the importance of the intracellular calcium signaling and its key function in the control of intracellular functions we were interested to study calcium homeostasis in FA. We found that FANCA cells display a dramatically low intracellular calcium concentration ([Ca(2+)]i) in resting conditions. This condition affects cellular responses to stress. The flux of Ca(2+) mobilized by H2O2 from internal stores is significantly lower in FANCA cells in comparison to controls. The low basal [Ca(2+)]i in FANCA appears to be an actively maintained process controlled by a finely tuned interplay between different intracellular Ca(2+) stores. The defects associated with the altered Ca(2+) homeostasis appear consistently overlapping those related to the unbalanced oxidative metabolism in FA cells underlining a contiguity between oxidative stress and calcium homeostasis.

SUBMITTER: Usai C

PROVIDER: S-EPMC4308711 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Mutated Fanconi anemia pathway in non-Fanconi anemia cancers.

Project description:An extremely high cancer incidence and the hypersensitivity to DNA crosslinking agents associated with Fanconi Anemia (FA) have marked it to be a unique genetic model system to study human cancer etiology and treatment, which has emerged an intense area of investigation in cancer research. However, there is limited information about the relationship between the mutated FA pathway and the cancer development or/and treatment in patients without FA. Here we analyzed the mutation rates of the seventeen FA genes in 68 DNA sequence datasets. We found that the FA pathway is frequently mutated across a variety of human cancers, with a rate mostly in the range of 15 to 35 % in human lung, brain, bladder, ovarian, breast cancers, or others. Furthermore, we found a statistically significant correlation (p < 0.05) between the mutated FA pathway and the development of human bladder cancer that we only further analyzed. Together, our study demonstrates a previously unknown fact that the mutated FA pathway frequently occurs during the development of non-FA human cancers, holding profound implications directly in advancing our understanding of human tumorigenesis as well as tumor sensitivity/resistance to crosslinking drug-relevant chemotherapy.

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The RPA inhibitor HAMNO sensitizes Fanconi anemia pathway-deficient cells.

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TLR8-dependent TNF-(alpha) overexpression in Fanconi anemia group C cells.

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Fanconi anemia genes are highly expressed in primitive CD34+ hematopoietic cells.

Project description:BACKGROUND: Fanconi anemia (FA) is a complex recessive genetic disease characterized by progressive bone marrow failure (BM) and a predisposition to cancer. We have previously shown using the Fancc mouse model that the progressive BM failure results from a hematopoietic stem cell defect suggesting that function of the FA genes may reside in primitive hematopoietic stem cells. METHODS: Since genes involved in stem cell differentiation and/or maintenance are usually regulated at the transcription level, we used a semiquantitative RT-PCR method to evaluate FA gene transcript levels in purified hematopoietic stem cells. RESULTS: We show that most FA genes are highly expressed in primitive CD34-positive and negative cells compared to lower levels in more differentiated cells. However, in CD34- stem cells the Fancc gene was found to be expressed at low levels while Fancg was undetectable in this population. Furthermore, Fancg expression is significantly decreased in Fancc -/- stem cells as compared to wild-type cells while the cancer susceptibility genes Brca1 and Fancd1/Brac2 are upregulated in Fancc-/- hematopoietic cells. CONCLUSIONS: These results suggest that FA genes are regulated at the mRNA level, that increased Fancc expression in LTS-CD34+ cells correlates with a role at the CD34+ differentiation stage and that lack of Fancc affects the expression of other FA gene, more specifically Fancg and Fancd1/Brca2, through an unknown mechanism.

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Project description:Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA.

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Project description:Transcriptomic comparison of stages of clonal evolution of Fanconi anemia modeled using induced pluripotent stem cells.

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VACTERL-H Association and Fanconi Anemia.

Project description:Patients with Fanconi anemia (FA) often have birth defects that suggest the diagnosis of VATER association. A review of 2,245 cases of FA reported in the literature from 1927 to 2012 identified 108 cases with at least 3 of the defining features of VATER association; only 29 had been so noted by the authors. The FA VATER signature was the significantly higher frequency of renal and limb (radial and/or thumb) anomalies (93% of cases had both) compared with less than 30% of VATER patients; the presence of one or both of these birth defects should lead to testing for FA. The relative frequencies of the genotypes of the patients with FA VATER were strikingly different from those expected from the general FA population; only 19% were FANCA, while 21% were FANCB, 14% FANCD1/BRCA2, and 12% FANCD2. Consistent with their genotypes, those with the FA VATER phenotype had a worse prognosis than FA patients with milder phenotypes, with shorter median survival and earlier onset of malignancies. The early identification of FA patients among infants with VATER association should lead to earlier more proactive management, such as cancer surveillance and genetic counseling.

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