Genetic disruption of both Fancc and Fancg in mice recapitulates the hematopoietic manifestations of Fanconi anemia
ABSTRACT Fanconi anemia (FA) is an inherited chromosomal instability syndrome characterized by bone marrow failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). Eight FA proteins associate in a nuclear core complex to monoubiquitinate FANCD2/FANCI in response to DNA damage. Additional functions have been described for some of the core complex proteins; however, in vivo genetic proof has been lacking. Here we show that double-mutant Fancc(-/-);Fancg(-/-) mice develop spontaneous hematologic sequelae including bone marrow failure, AML, MDS and complex random chromosomal abnormalities that the single-mutant mice do not. This genetic model provides evidence for unique core complex protein function independent of their ability to monoubiquitinate FANCD2/FANCI. Importantly, this model closely recapitulates the phenotypes found in FA patients and may be useful as a preclinical platform to evaluate the molecular pathogenesis of spontaneous bone marrow failure, MDS and AML in FA.
Full-textDOI: · Available from: Grzegorz Nalepa, Aug 25, 2015
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- "The first double-mutant mice reported, Fanca−/− Fancc−/−, show no evidence of an additive phenotype, suggesting an epistatic relationship between the two genes (Noll et al., 2002). However, Fancc−/− Fancg−/− double-mutant mice have a broader phenotype: the mice develop BMF, myelodysplasia and complex cytogenetic abnormalities, which are phenotypes that were not present in either single knockout mouse strain (Pulliam-Leath et al., 2010). It was suggested that this non-epistatic relationship between Fancc and Fancg revealed a unique function for Fancg, because an additive phenotype was not observed in Fanca−/− Fancc−/− double-mutant mice. "
ABSTRACT: Fanconi anaemia (FA) is a rare autosomal recessive or X-linked inherited disease characterised by an increased incidence of bone marrow failure (BMF), haematological malignancies and solid tumours. Cells from individuals with FA show a pronounced sensitivity to DNA interstrand crosslink (ICL)-inducing agents, which manifests as G2-M arrest, chromosomal aberrations and reduced cellular survival. To date, mutations in at least 15 different genes have been identified that cause FA; the products of all of these genes are thought to function together in the FA pathway, which is essential for ICL repair. Rapidly following the discovery of FA genes, mutant mice were generated to study the disease and the affected pathway. These mutant mice all show the characteristic cellular ICL-inducing agent sensitivity, but only partially recapitulate the developmental abnormalities, anaemia and cancer predisposition seen in individuals with FA. Therefore, the usefulness of modelling FA in mice has been questioned. In this Review, we argue that such scepticism is unjustified. We outline that haematopoietic defects and cancer predisposition are manifestations of FA gene defects in mice, albeit only in certain genetic backgrounds and under certain conditions. Most importantly, recent work has shown that developmental defects in FA mice also arise with concomitant inactivation of acetaldehyde metabolism, giving a strong clue about the nature of the endogenous lesion that must be repaired by the functional FA pathway. This body of work provides an excellent example of a paradox in FA research: that the dissimilarity, rather than the similarity, between mice and humans can provide insight into human disease. We expect that further study of mouse models of FA will help to uncover the mechanistic background of FA, ultimately leading to better treatment options for the disease.Disease Models and Mechanisms 01/2013; 6(1):40-7. DOI:10.1242/dmm.009795 · 4.97 Impact Factor
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- "While the Btbd12−/−/Fancp−/− mouse is the only single FA gene loss of function model to recapitulate some aspects of the BMF seen in patients, the compound loss of function of Fancc−/− and Fancg−/− also results in spontaneous hematologic defects including BMF, AML, MDS, and complex random chromosomal abnormalities . This would again seem at odds with the idea that the FA signaling pathway is epistatic and suggests that some of the FA proteins have divergent functions. "
ABSTRACT: Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC). This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients.Anemia 05/2012; 2012(1):265790. DOI:10.1155/2012/265790
Conference Paper: Mission Interactive Scenario Studio (MISS) for autonomous spacecraft[Show abstract] [Hide abstract]
ABSTRACT: We propose building a studio enabling the use of diverse existing mission activity and scenario patterns, the creation of new ones, and the modeling of their effects using existing modeling tools. The core of the studio is a component-based type library, which captures years of mission adaptation patterns in various forms. The studio works as a content server to capture the developed adaptation knowledge for reuse and provides bringing into different mission uplink implementations, including the Mission Data System (MDS) based on D. Dvorak et al. (2000) state/goal machinery. Various activities can be coordinated, controlled, and reused through the studio's component interface to establish and model a mission scenario. A special component factory mechanism is in place to facilitate the adaptation of projects into the studio. The architecture of the studio reflects and enforces a division of knowledge and actions into three parts: model, view, controller, (MVC). The model contains information about (a proposed version of) the spacecraft and mission. The controller contains logic for constructing scenarios of mission activities. The information in the model and controller is principally in the form of reusable patterns. For example, Activity Plan Generator (Apgen) according to P. Maldague et al. (1997) and P. Maldague et al. (1999) is one possible viewer; MDS is another. A 3-tiered infrastructure is used for the studio, reflecting the model, controller, viewer architecture. The studio is useful in pre-phase A of a project by enabling spacecraft design options to be played against desired mission scenarios. In later design options to be played against desired mission scenarios. In later design phases of a project, the construction and modeling of more detailed scenario is supported by the studio.Aerospace Conference, 2003. Proceedings. 2003 IEEE; 02/2003