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Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE120169 | GEO | 2018/11/30

REPOSITORIES: GEO

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Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia.

Project description:Fanconi anemia (FA) causes bone marrow failure early during childhood, and recent studies indicate that a hematopoietic defect could begin in utero. We performed a unique kinetics study of hematopoiesis in Fancg-/- mouse embryos, between the early embryonic day 11.5 (E11.5) to E12.5 developmental window (when the highest level of hematopoietic stem cells [HSC] amplification takes place) and E14.5. This study reveals a deep HSC defect with exhaustion of proliferative and self-renewal capacities very early during development, together with severe FA clinical and biological manifestations, which are mitigated at E14.5 due to compensatory mechanisms that help to ensure survival of Fancg-/- embryos. It also reports that a deep HSC defect is also observed during human FA development, and that human FA fetal liver (FL) HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg-/- FL HSCs. Altogether, our results highlight that early mouse FL could represent a good alternative model for studying Fanconi pathology.

| S-EPMC6234961 | biostudies-literature

Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia [human]

Project description:We performed a unique kinetics study of hematopoiesis in Fancg-/- mouse embryos, between E12.5 and E14.5 developmental window. We also report for the first time that a deep HSC defect is also observed during human FA development, and that human FA FL HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg-/- FL HSCs.

2018-11-30 | GSE120168 | GEO

Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia [mouse]

2018-11-30 | GSE120167 | GEO

Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia

Project description:Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia

| PRJNA491828 | ENA

Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia [mouse]

Project description:Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia [mouse]

| PRJNA491829 | ENA

Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia [human]

Project description:Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia [human]

| PRJNA491830 | ENA

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.

| S-EPMC4653013 | biostudies-literature

Pluripotent cell models of fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors.

Project description:Fanconi anemia (FA) is a disorder of genomic instability characterized by progressive bone marrow failure (BMF), developmental abnormalities, and an increased susceptibility to cancer. Although various consequences in hematopoietic stem/progenitor cells have been attributed to FA-BMF, the quest to identify the initial pathological event is still ongoing. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts of six patients with FA and FANCA mutations. An improved reprogramming method yielded iPSC-like colonies from all patients, and iPSC clones were propagated from two patients. Quantitative evaluation of the differentiation ability demonstrated that the differentiation propensity toward the hematopoietic and endothelial lineages is already defective in early hemoangiogenic progenitors. The expression levels of critical transcription factors were significantly downregulated in these progenitors. These data indicate that the hematopoietic consequences in FA patients originate from the early hematopoietic stage and highlight the potential usefulness of iPSC technology for elucidating the pathogenesis of FA-BMF.

| S-EPMC4367500 | biostudies-literature

Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype.

Project description:Fanconi anemia (FA) is a human genetic disease characterized by chromosome instability, cancer predisposition, and cellular hypersensitivity to DNA crosslinking agents. The FA pathway regulates the repair of DNA crosslinks. A critical step in this pathway is the monoubiquitination and deubiquitination of FANCD2. Deubiquitination of FANCD2 is mediated by the ubiquitin protease, USP1. Here, we demonstrate that targeted deletion of mouse Usp1 results in elevated perinatal lethality, male infertility, crosslinker hypersensitivity, and an FA phenotype. Usp1(-/-) mouse embryonic fibroblasts had heightened levels of monoubiquitinated Fancd2 in chromatin. Usp1(-/-) cells exhibited impaired Fancd2 foci assembly and a defect in homologous recombination repair. Double knockout of Usp1 and Fancd2 resulted in a more severe phenotype than either single knockout. Our results indicate that mouse Usp1 functions downstream in the FA pathway. Deubiquitination is a critical event required for Fancd2 nuclear foci assembly, release from chromatin, and function in DNA repair.

| S-EPMC3134285 | biostudies-literature

Pluripotent cell models of Fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors

Project description:Fanconi anemia (FA) is a disorder of genomic instability characterized by progressive bone marrow failure (BMF), developmental abnormalities and an increased susceptibility to cancer. Although various consequences in hematopoietic stem/progenitor cells have been attributed to FA-BMF, the quest to identify the initial pathological event is still ongoing. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts of six FA patients with FANCA mutations. An improved reprogramming method yielded iPSC-like colonies from all patients, and iPSC clones were propagated from two patients. Quantitative evaluation of the differentiation ability demonstrated that the differentiation propensity toward the hematopoietic and endothelial lineages is already defective in early hemoangiogenic progenitors. The expression levels of critical transcription factors were significantly downregulated in these progenitors. These data indicate that the hematopoietic consequences in FA patients originate from the early hematopoietic stage, and highlight the potential usefulness of iPSC technology for elucidating the pathogenesis of FA-BMF.

2015-02-03 | GSE65507 | GEO

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