Hematopoietic Stem Cells from
            <i>Fancc</i>
            <sup>−/−</sup>
            Mice Have Lower Growth and Differentiation Potential in Response to Growth Factors

Aubé, Michel; Lafrance, Matthieu; Charbonneau, Chantal; Goulet, Isabelle; Carreau, Madeleine

doi:10.1634/stemcells.20-5-438

Cited by 15 publications

(11 citation statements)

References 51 publications

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“…72 Unfortunately, mouse models harboring a disrupted mouse homolog of FANCC fail to develop MDS. 73 However, the double mutant Fancc -/-, Fancg -/-mice develop spontaneous hematologic abnormalities including BM failure, AML, MDS and complex random chromosomal abnormalities that the single mutant mice do not display. 74 …”

Section: Genomic Instability (Gi)mentioning

confidence: 99%

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

2012

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Myelodysplastic syndromes represent particularly challenging hematologic malignancies that arise from a large spectrum of genetic events resulting in a disease characterized by a range of different presentations and outcomes. Despite efforts to classify and identify the key genetic events, little improvement has been made in therapies that will increase patient survival. Animal models represent powerful tools to model and study human diseases and are useful pre-clinical platforms. In addition to enforced expression of candidate oncogenes, gene inactivation has allowed the consequences of the genetic effects of human myelodysplastic syndrome to be studied in mice. This review aims to examine the animal models expressing myelodysplastic syndrome-associated genes that are currently available and to highlight the most appropriate model to phenocopy myelodysplastic syndrome disease and its risk of transformation to acute myelogenous leukemia. ©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.069385 ABSTRACTMouse models myelodysplastic syndrome human candidate genes haematologica | 2013; 98 (1) 11 Figure 1. Mouse models to study malignant hematologic disease. Several strategies can be employed to create mouse models of disease. Candidate genes can be introduced into the germline under the control of appropriate promoters to drive expression in certain cell compartments. Knock-out strategies create gene deficient mice, whilst knock-in strategies use the endogenous promoters; but again these tend to be conditional systems requiring specific promoters to determine in which cell the genes are introduced. Transduction of bone marrow and reinfusion is a powerful tool. Xenograft models are theoretically the best if the techniques involved can be improved.

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Section: Genomic Instability (Gi)mentioning

confidence: 99%

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

2012

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“…This is substantiated by the observation that bone marrow cells isolated from FancC -/- mice have a significantly decreased short-term and long-term, multi-lineage repopulating ability in competitive transplantation assays (4, 7, 27). This was attributed to impaired ability of FancC -/- hematopoietic stem cells to differentiate and self-renew in response to stimulatory growth factors and cytokines (3, 23). The defect in repopulating capacity of FancC -/- bone marrow cells is corrected by retroviral-mediated gene transfer of FancC (28), demonstrating that FANCC and the FA pathway are specifically required for the maintenance of HSC function in vivo.…”

Section: Fancc-/- Micementioning

confidence: 99%

Mouse models of Fanconi anemia

Parmar

D’Andrea

Niedernhofer

2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

148

122

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Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, thirteen complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability. Keywordsinterstrand crosslinks; gene targeting; mouse models; genome instability; tumors; stem cells Fanconi anemiaFanconi anemia is a rare autosomal recessive disease with a complex spectrum of symptoms including congenital skeletal and renal anomalies, growth retardation, pigmentation abnormalities, fertility defects, aplastic anemia, and increased risk of acute myeloid leukemia and epithelial tumors (see "Fanconi Anemia and its Diagnosis" Auerbach, this issue). Progressive bone marrow failure and late-developing myeloid malignancies account for 90% of mortality in FA patients. Bone marrow failure in FA children is attributed to the excessive apoptosis and subsequent failure of the hematopoietic stem cell compartment. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia (FA) pathway, a response mechanism to replicative stress (33). To date, thirteen complementation groups of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptMutat Res. Author manuscript; available in PMC 2010 July 31. by clinical suspicion coupled with detecting an increased number of chromosomal aberrations in patient cells exposed to drugs that induce DNA interstrand crosslinks (ICLs). ICLs covalently tether both strands of the DNA helix together and therefore are an absolute block to the progression of a replication fork and a potent inducer of replication stress. Crosslinking agents induce replication-dependent double-strand breaks (DSBs) (54). These DSBs are subsequently repaired by homologous ...

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“…However, in the context of clinical gene therapy, sufficient numbers of hematopoietic stem/progenitors cells from FA patients are difficult to obtain even following G-CSF-mobilization [28]. Furthermore, ex vivo culture for gene transfer is deleterious for FA cells and in retrospect would possibly explain the poor success rate of earlier gene therapy trials in FA patients [11–13, 17]. Our data now provides an alternative to ex vivo gene transfer approaches showing the efficacy of direct intrafemoral gene delivery in correcting the hematopoietic defects in FA.…”

Section: Discussionmentioning

confidence: 99%

“…Several reasons may account for the poor success rate of these trails, for instance, the low availability of HSC found in FA patients even before severe pancytopenia [10], the reduced reconstitution ability and self-renewal capacity of FA-deficient HSC following culture [12, 13], the development of aberrant clones of FA-deficient HSC following ex vivo culture [13], as well as defective homing properties of FA-deficient BM cells [14]. Although rapid transduction of FA cells using short-term culture [15] or culture in the presence of an antioxidant [16] improved FA cell survival, these approaches still make use of cytokines and growth factors that may affect long-term HSC function [12, 17]. Thus, targeting HSC directly in their environment would ensure maintenance of their function and enable the correction of the remaining stem cells.…”

Section: Introductionmentioning

confidence: 99%

Correction of Fanconi Anemia Group C Hematopoietic Stem Cells Following Intrafemoral Gene Transfer

Habi

Girard

Bourdages

et al. 2010

Anemia

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The main cause of morbidity and mortality in Fanconi anemia patients is the development of bone marrow (BM) failure; thus correction of hematopoietic stem cells (HSCs) through gene transfer approaches would benefit FA patients. However, gene therapy trials for FA patients using ex vivo transduction protocols have failed to provide long-term correction. In addition, ex vivo cultures have been found to be hazardous for FA cells. To circumvent negative effects of ex vivo culture in FA stem cells, we tested the corrective ability of direct injection of recombinant lentiviral particles encoding FancC-EGFP into femurs of FancC −/− mice. Using this approach, we show that FancC −/− HSCs were efficiently corrected. Intrafemoral gene transfer of the FancC gene prevented the mitomycin C-induced BM failure. Moreover, we show that intrafemoral gene delivery into aplastic marrow restored the bone marrow cellularity and corrected the remaining HSCs. These results provide evidence that targeting FA-deficient HSCs directly in their environment enables efficient and long-term correction of BM defects in FA.

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Hematopoietic Stem Cells from Fancc ^−/− Mice Have Lower Growth and Differentiation Potential in Response to Growth Factors

Abstract: ABSTRACT

Cited by 15 publications

References 51 publications

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

Mouse models of Fanconi anemia

Correction of Fanconi Anemia Group C Hematopoietic Stem Cells Following Intrafemoral Gene Transfer

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Hematopoietic Stem Cells from Fancc −/− Mice Have Lower Growth and Differentiation Potential in Response to Growth Factors

Abstract: ABSTRACT

Cited by 15 publications

References 51 publications

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

Mouse models of Fanconi anemia

Correction of Fanconi Anemia Group C Hematopoietic Stem Cells Following Intrafemoral Gene Transfer

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Hematopoietic Stem Cells from Fancc ^−/− Mice Have Lower Growth and Differentiation Potential in Response to Growth Factors