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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65507 | GEO | 2015/02/03

SECONDARY ACCESSION(S): PRJNA274249

REPOSITORIES: GEO

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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. The investigation of the RNA-seq analysis of iPSC-derived HAPCs.

2015-02-03 | E-GEOD-65507 | biostudies-arrayexpress

Global gene expression analysis for neuron stem cells (NSC) derived from iPSCs with Fanconi Anemia

2014-06-14 | GSE40865 | GEO

Global gene expression analysis for neuron stem cells (NSC) derived from iPSCs with Fanconi Anemia

Project description:Fanconi Anemia (FA) is a recessive disorder associated with genomic instability We generated iPSC from FA patient fibroblasts and further corrected the mutated FANCA gene with a homologous recombination-based approach. The NSCs were differentiated from control-iPSCs, FA-iPSCs, and corrected FA-NSCs, and their gene expressions were determined by microarray analysis.

2014-06-14 | E-GEOD-40865 | biostudies-arrayexpress

Efficient differentiation of human Fanconi anemia hematopoietic progenitor cells by inducible complementation reveals a role for p53 in regulation of self-renewal and differentiation

Project description:Fanconi anemia (FA) is a genetic disorder of DNA repair that manifests as bone marrow dysfunction typically occurring in childhood. The lack of human model systems has impeded progress in identifying effective therapies. To address this, efforts have focused on using directed differentiation of patient-derived human induced pluripotent stem cells (IPSCs) to hematopoietic stem and progenitor cells (HSPCs). However, the requirement for an intact FA DNA repair pathway for efficient reprogramming of patient cells to pluripotency requires genetic complementation of FA pathway defects to efficiently generate IPSCs, precluding derivation of FA pathway-deficient human HSPCs for study. To overcome this barrier, we employed a system of doxycycline-inducible complementation of FANCA deficient patient-derived IPS cells. Doxycycline exposure allowed for the robust maintenance of undifferentiated IPS cells in culture. Removal or retention of doxycycline exposure during directed differentiation of HSPCs allowed for the production of isogenic FANCA-deficient and FANCA-complemented human HSPCs. IPS-derived, FANCA-deficient HSPCs showed impaired response to genotoxic stress, proliferation, and survival compared to complemented HSPCs. Using these cells, we found that FANCA-deficient HSPCs showed expected impaired clonogenicity in methylcellulose culture and unexpected accelerated erythroid differentiation relative to complemented cells. Activation of p53-mediated p21 transactivation in FANCA-deficient HSPCs serves to drive accelerated erythropoiesis as the expense of clonogenicity. This study demonstrates the feasibility of inducible complementation in IPSCs as a method to generate isogenic FA-deficient and FA-complemented human HPSCs for disease modeling and uncovers a novel mechanism by which the FA pathway regulates the balance between stem cell maintenance and terminal differentiation.

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The Splicing Factor CCAR1 Regulates the Fanconi Anemia/BRCA Pathway

Project description:The twenty-three Fanconi Anemia proteins cooperate in a DNA repair pathway, called the FA/BRCA pathway, required for the monoubiquitination of FANCD2 and the excision of interstrand DNA crosslinks (ICLs). The CCAR1 (cell division cycle and apoptosis regulator 1) protein is also a regulator of ICL repair, though its possible function in the FA/BRCA pathway remains unknown. Here, we demonstrate that CCAR1 plays a unique upstream role in the FA/BRCA pathway and is required for FANCA protein expression and FANCD2 monoubiquitination. Interestingly, loss of CCAR1 results in retention of a poison exon in the FANCA transcript, thereby leading to reduced FANCA protein expression. A unique domain of CCAR1, the so-called EF-hand domain, binds to the spliceosome SF3B complex and is required for its mRNA splicing activity. Taken together, CCAR1 is a unique splicing factor, required for normal splicing of the FANCA mRNA and perhaps other mRNAs involved in various cellular pathways.

2024-08-21 | GSE242781 | GEO

In Fanconi Anemia, impaired accumulation of bone marrow neutrophils during emergency granulopoiesis induces hematopoietic stem cell stress

Project description:Fanconi Anemia (FA) is an inherited disorder of DNA-repair caused by mutation in one of 20+ interrelated genes that repair intra-strand DNA crosslinks and rescue collapsed or stalled replication forks. The most common hematologic abnormality in FA is anemia, but progression to bone marrow failure (BMF), clonal hematopoiesis, or acute myeloid leukemia (AML) may also occur. In prior studies, we found that Fanconi DNA-repair is required for successful emergency granulopoiesis; the process for rapid neutrophil production during the innate immune response. Specifically, Fancc-/- mice did not develop neutrophilia in response to emergency granulopoiesis stimuli, but instead exhibited apoptosis of bone marrow hematopoietic stem cells (HSCs) and differentiating neutrophils. Repeated emergency granulopoiesis challenges induced BMF in most Fancc-/- mice, with AML in survivors. In contrast, we found equivalent emergency granulopoiesis-induced neutrophilia in Fancc-/-Tp53+/- mice and wild type (WT) mice, without BMF in either. Since bone marrow neutrophil accumulation triggers termination of emergency granulopoiesis, we hypothesize neutrophilia protects Fancc-/-Tp53+/- bone marrow from the stress of sustained inflammatory physiology, as experienced by Fancc-/- mice.

2024-08-28 | GSE267161 | GEO

Modeling Fanconi Anemia pathogenesis and therapeutics using integration-free patient iPSCs

Project description:To elucidate the transcriptional and epigenetic alterations underlying the neurogenic defects of FA-NSCs, we conducted gene expression microarray analysis and global DNA methylation profiling. The gene expression pattern of gene-corrected NSCs (C-FA-NSCs) resembled that of control-NSCs but clustered distantly from FA-NSCs (Fig. 6F and Table S1). Hierarchical clustering based on DNA methylation levels in the promoter region (+/-1.5kb from TSS) of genes whose expression levels were rescued in C-FA-NSCs, placed C-FA-NSCs closer to control-NSCs and away from FA-NSCs (Fig. 6G), although this pattern was not seen at the whole genome level (Fig. S4C). This suggests that FANCA gene correction leads to specific methylation changes in a subset of promoters.

2014-05-15 | GSE57685 | GEO

Modeling Fanconi Anemia pathogenesis and therapeutics using integration-free patient iPSCs

2014-05-15 | E-GEOD-57685 | biostudies-arrayexpress

MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia

Project description:We profiled primary HSPCs from Fanconi anemia (FA) patients for single cell transcriptome (scRNA-seq) to identify additional determinants of HSPC impairment leading to the bone marrow failure,. Trajectory analysis revealed that early hematopoietic differentiation potential is preserved in FA HSPCs. As expected, p53 and TGFβ pathway genes were overexpressed in HSPCs from FA patients. The oncogene MYC was also identified as one of the top over-expressed genes in FA HSPCs. Interestingly, we observed co-existence of “High-TP53” expressing HSPCs and HighMYC expressing HSPCs in FA bone marrow. Inhibition of MYC expression by the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of primary HSPCs from FA patients but rescued the physiological/genotoxic stress in HSPCs from FA mice. The “High-MYC” expressing HSPCs exhibited a significant downregulation of cell adhesion genes, such as CXCR4. Consistently, HSPCs in FA patients showed a defect in adhesion to their bone marrow niche resulting in egression from the bone marrow into peripheral blood. We speculate that MYC overexpression impairs HSPC function and contributes to exhaustion of HSPCs in FA bone marrow.

2020-09-08 | GSE157591 | GEO

EndoC-betaH3 Cell FANCA Protein Interactions Regulated by Glucose Stimulation

Project description:Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas β cells is unknown. Therefore, we sought to identify previously unexplored roles of FA proteins in the glucose responsive human pancreas β cell line EndoC-βH3 using a mass spectrometry-based protein interaction analysis of endogenous FANCA. This study reveals glucose stimulation-dependent changes in the FANCA interaction network indicative of the DNA damage response (DDR) through interactions with other FA proteins. We identify protein interactions with FANCA related to β cell insulin secretion.

2019-07-25 | PXD010589 | Pride

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