Why does the bone marrow fail in Fanconi anemia?

Garaycoechea, Juan I.; Patel, Ketan

doi:10.1182/blood-2013-09-427740

Cited by 139 publications

(132 citation statements)

References 90 publications

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“…Most strikingly, those patients entirely deficient for ALDH2 developed BMF within the first 7 months of life (Hira et al, 2013). Patel's laboratory has demonstrated that blocking ADH5 (formaldehyde dehydrogenase) or ALDH2 triggered DNA damage and was indeed genotoxic to hematopoietic stem cells, causing FA mice to spontaneously develop acute leukemia and profound BMF (Garaycoechea et al, 2012;Garaycoechea and Patel, 2014;Langevin et al, 2011). These reports confirm unequivocally that endogenous aldehydes are sufficient to cause DNA damage and induce leukemia and BMF in both humans and mice deficient in aldehyde detoxification and DNA repair.…”

Section: Discussionsupporting

confidence: 67%

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Yu¹,

Lai²,

Hartwell³

et al. 2015

Toxicol. Sci.

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Formaldehyde is not only a widely used chemical with well-known carcinogenicity but is also a normal metabolite of living cells. It thus poses unique challenges for understanding risks associated with exposure. N 2-hydroxymethyl-dG (N 2 -HOMedG) is the main formaldehyde-induced DNA mono-adduct, which together with DNA-protein crosslinks (DPCs) and toxicityinduced cell proliferation, play important roles in a mutagenic mode of action for cancer. In this study, N 2 -HOMe-dG was shown to be an excellent biomarker for direct adduction of formaldehyde to DNA and the hydrolysis of DPCs. The use of inhaled [ 13 CD 2 ]-formaldehyde exposures of rats and primates coupled with ultrasensitive nano ultra performance liquid chromatography-tandem mass spectrometry permitted accurate determinations of endogenous and exogenous formaldehyde DNA damage. The results show that inhaled formaldehyde only reached rat and monkey noses, but not tissues distant to the site of initial contact. The amounts of exogenous adducts were remarkably lower than those of endogenous adducts in exposed nasal epithelium. Moreover, exogenous adducts accumulated in rat nasal epithelium over the 28-days exposure to reach steady-state concentrations, followed by elimination with a half-life (t 1/2 ) of 7.1 days. Additionally, we examined artifact formation during DNA preparation to ensure the accuracy of nonlabeled N 2 -HOMe-dG measurements. These novel findings provide critical new data for understanding major issues identified by the National Research Council Review of the 2010 Environmental Protection Agency's Draft Integrated Risk Information System Formaldehyde Risk Assessment. They support a data-driven need for reflection on whether risks have been overestimated for inhaled formaldehyde, whereas underappreciating endogenous formaldehyde as the primary source of exposure that results in bone marrow toxicity and leukemia in susceptible humans and rodents deficient in DNA repair.

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Section: Discussionsupporting

confidence: 67%

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage

Yu¹,

Lai²,

Hartwell³

et al. 2015

Toxicol. Sci.

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“…Most FA patients develop bone marrow failure culminating in pancytopenia, with a median age at presentation of 7 years. 9 Our patient had normal blood counts at birth, which is expected in patients with FA. It is important to note that As abnormalities present, thorough hematologic testing is warranted because patients are at high risk of developing myelodysplastic syndrome and acute myelogenous leukemia, both of which were ultimately present in our patient.…”

Section: Multiorgan Involvementmentioning

confidence: 90%

A Review of Fanconi Anemia for the Practicing Pediatrician

Triemstra¹,

Pham²,

Rhodes³

et al. 2015

Pediatr Ann

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Early recognition of a patient who might have Fancomi anemia by the general pediatrician and referral to a tertiary care center with a dedicated cancer risk program is critical for early diagnosis. Genetic testing and close multidisciplinary surveillance is required for patients with this syndrome and their families because of its multisystem involvement and propensity for early-onset bone marrow failure and leukemic transformation. This article reviews the clinical symptoms and signs, radiologic findings, and screening guidelines of FA for the general pediatrician.

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“…). Le temps néces-saire à la tumeur pour se développer pourrait aussi être plus long que l'espérance de vie des souris [37], et tant que les cellules AF ne sont pas dans un contexte stressant (forcées à se mobiliser pour repeupler la moelle osseuse ou à se répliquer), elles parviennent à compenser leur faible du voisinage chromosomique des gènes Fanc [18]. L'existence de la mono-ubiquitination de FANCD2 confirme la fonctionnalité de la voie FA-BRCA chez cet organisme [19].…”

Section: Les Découvertes Majeures Apportées Par Les Modèles Animaux Punclassified