Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia

Tischkowitz, Marc; Morgan, Neil V.; Grimwade, David; Eddy, C; Ball, Sarah E.; Vořechovský, Igor; Langabeer, Stephen E.; Stöger, Reinhard; Hodgson, Shirley; Mathew, Christopher G.

doi:10.1038/sj.leu.2403280

Cited by 75 publications

(46 citation statements)

References 41 publications

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“…Other cancers that have been reported to be associated with heterozygous mutation of a FA gene include BRCA2/FANCD1 related prostate cancer, gastric cancer, and melanoma (Liede et al 2004), FANCA related acute myeloid leukemia (Condie et al 2002;Tischkowitz et al 2004), and FANCC related acute lymphoblastic leukemia (Rischewski et al 2000).…”

Section: Cancer Risk In Heterozygous Carriers Of Fa Gene Mutationmentioning

confidence: 99%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

364

345

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Over the past few years, study of the rare inherited chromosome instability disorder, Fanconi Anemia (FA), has uncovered a novel DNA damage response pathway. Through the cooperation of multiple proteins, this pathway regulates a complicated cellular response to DNA cross-linking agents and other genotoxic stresses. In this article we review recent data identifying new components of the FA pathway that implicate it in several aspects of the DNA damage response, including the direct processing of DNA, translesion synthesis, homologous recombination, and cell cycle regulation. We also discuss new findings that explain how the FA pathway is regulated through the processes of ubiquitination and deubiquitination. We then consider the clinical implications of our current understanding of the FA pathway, particularly in the development and treatment of malignancy in heterozygous carriers of FA mutations or in patients with sporadic cancers. We consider how recent studies of p53-mediated apoptosis and loss of p53 function in models of FA may help explain the clinical features of the disease and finally present a hypothesis to account for the specificity of the FA pathway in the response to DNA cross-links.

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Section: Cancer Risk In Heterozygous Carriers Of Fa Gene Mutationmentioning

confidence: 99%

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Kennedy¹,

D’Andrea²

2005

Genes Dev.

364

345

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“…This suggests that functional Fanconi proteins are essential to prevent AML [24]. Few stringent genotype-phenotype connections have emerged for Fanconi anemia.…”

Section: Mutations In Fanconi Anemia Genesmentioning

confidence: 99%

Inherited mutations impair responses to environmental carcinogens: Cancer prevention in mutation carriers

Friedenson¹

2011

Nat Prec

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Some environmental carcinogens may be responsible for a modest increase in the numbers of cancers after years of exposure. Economic or political factors weigh against widespread bans of carcinogens. However, lists of chemicals and agents that cause cancer assume that everyone is equally susceptible to their carcinogenic effects.Hereditary cancer gene mutations can target specific tissues if they are exposed to a carcinogen and the hereditary deficit impairs normal protective responses. Mutation carriers should then have higher risks for specific cancers caused by specific carcinogens.For example, it can be predicted that BRCA1 or BRCA2 mutation carriers should be highly susceptible to the carcinogen formaldehyde. High formaldehyde levels can overwhelm normal enzyme detoxification systems or detoxification genes may be inadequate or missing. Formaldehyde that is not detoxified causes strands of DNA to cross-link to each other and to nearby proteins. Carriers of mutations in BRCA1/2 dependent pathways are deficient in the ability to undo these cross-links.

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“…1 FA gene FANCA has been previously identified as having reduced expression 13 or point mutations 14 in a number of adult AML patients. Mutations in ATM, NBS1 and DNL IV have also been previously identified in leukemia.…”

Section: Brca2mentioning

confidence: 99%

Chromosomal instability syndromes are sensitive to poly ADP-ribose polymerase inhibitors

Gaymes¹,

Shall²,

Farzaneh³

et al. 2008

Haematologica

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Poly ADP-ribose polymerase inhibitors have been shown to target cells with homologous recombination DNA repair defects. We report that poly ADP-ribose polymerase inhibitors induces apoptosis in cells deficient in other key DNA repair components. Chromosomal instability disorders, Fanconi Anemia and Bloom's syndrome have dysfunctional DNA repair and an increased likelihood of leukemic transformation. PI addition to Fanconi Anemia and Bloom's syndrome cells resulted in significant apoptosis. Furthermore, poly ADP-ribose polymerase inhibitors induced apoptosis in DNA repair signaling defective ATM -/-and NBS -/-fibroblasts. Immunocytochemistry showed homologous recombination was abrogated in NBS -/-and ATM -/-fibroblasts, compromised in Fanconi anemia and normal in Bloom's syndrome cells in response to poly ADP-ribose polymerase inhibitors. Strikingly, poly ADP-ribose polymerase inhibitors increases non-homologous end joining repair activity, whilst non-homologous end joining deficient cells are extremely sensitive to poly ADP-ribose polymerase inhibitors. These data suggest poly ADP-ribose polymerase inhibitors target cells with DNA repair and signaling defects rather than solely defects in homologous recombination improving the potential of poly ADP-ribose polymerase inhibitors therapy in a wider range of cancers.

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Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia

Cited by 75 publications

References 41 publications

The Fanconi Anemia/BRCA pathway: new faces in the crowd

The Fanconi Anemia/BRCA pathway: new faces in the crowd

Inherited mutations impair responses to environmental carcinogens: Cancer prevention in mutation carriers

Chromosomal instability syndromes are sensitive to poly ADP-ribose polymerase inhibitors

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