Genotoxic aldehydes in the hematopoietic system

Wang, Meng; Dingler, Felix A.; Patel, Ketan

doi:10.1182/blood.2019004316

Cited by 32 publications

(21 citation statements)

References 111 publications

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“…What is not controversial is a clear and emerging consensus that multiple genetic factors can influence the penetrance of the FA phenotype. The most compelling of these are studies from Patel and colleagues demonstrating that deficits in ethanol metabolism robustly induce a classic FA phenotype in FA deficient mice [ 59 , 60 , 61 , 62 , 63 ]. There are additional cellular changes that have the capacity to impact development of the FA phenotype, for example dysregulated TGF-β signaling [ 64 ] and MAD2 defects [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs

Meek

Yang

Takada

et al. 2022

Genes

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Bernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. Studies have identified several loci to be associated with predisposition to HS in BMDs, including near the MTAP/CDKN2A region, but no causative coding variant has been identified. Here we report the presence of a coding polymorphism in the gene encoding FANCG, near the MTAP/CDKN2A locus. This variant is in a conserved region of the protein and appears to be specific to BMDs. Canine fibroblasts derived from dogs homozygous for this variant are hypersensitive to cisplatin. We show this canine FANCG variant and a previously defined hypomorphic FANCG allele in humans impart similar defects in DNA repair. However, our data also indicate that this variant is neither necessary nor sufficient for the development of HS. Furthermore, BMDs homozygous for this FANCG allele display none of the characteristic phenotypes associated with Fanconi anemia (FA) such as anemia, short stature, infertility, or an earlier age of onset for HS. This is similar to findings in FA deficient mice, which do not develop overt FA without secondary genetic mutations that exacerbate the FA deficit. In sum, our data suggest that dogs with deficits in the FA pathway are, like mice, innately resistant to the development of FA.

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Section: Discussionmentioning

confidence: 99%

Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs

Meek

Yang

Takada

et al. 2022

Genes

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“…Fanconi anemia is a rare disease caused by mutations in DNA repair genes and characterized by bone marrow failure, developmental abnormalities and multiple cancer predisposition ( Auerbach, 2009 ; Kee and D'Andrea, 2012 ). Evidence has shown that naturally occurring and endogenous genotoxic aldehydes, such as formaldehyde and acetaldehyde, could be primary sources of DNA damage that induce genome instability in hemopoietic stem cells in Fanconi anemia patients ( Wang et al, 2022 ; Garaycoechea and Patel, 2014 ; Brooks and Zakhari, 2014 ). Hira et al showed that ALDH2 deficiency accelerated bone marrow failure in pediatric patients with Fanconi anemia ( Hira et al, 2013 ).…”

Section: Aldh2 Metabolism and Disease Beyond Alcoholmentioning

confidence: 99%

ALDH2 variance in disease and populations

Chen

Kraemer

Mochly‐Rosen

2022

Disease Models &Amp; Mechanisms

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The ALDH2*2 missense variant that commonly causes alcohol flushing reactions is the single genetic polymorphism associated with the largest number of traits in humans. The dysfunctional ALDH2 variant affects nearly 8% of the world population and is highly concentrated among East Asians. Carriers of the ALDH2*2 variant commonly present alterations in a number of blood biomarkers, clinical measurements, biometrics, drug prescriptions, dietary habits and lifestyle behaviors, and they are also more susceptible to aldehyde-associated diseases, such as cancer and cardiovascular disease. However, the interaction between alcohol and ALDH2-related pathology is not clearly delineated. Furthermore, genetic evidence indicates that the ALDH2*2 variant has been favorably selected for in the past 2000-3000 years. It is therefore necessary to consider the disease risk and mechanism associated with ALDH2 deficiency, and to understand the possible beneficial or protective effect conferred by ALDH2 deficiency and whether the pleiotropic effects of ALDH2 variance are all mediated by alcohol use.

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“…Recent studies in genetically modified mouse models combining deficiency of the aldehyde detoxification system and the FA pathway deficiency point to acetaldehyde and formaldehyde as important endogenous aldehydes that create ICLs [11][12][13] . Detoxifying enzymesacetaldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 5 (ADH5)are required to metabolize these reactive aldehydes and prevent stem cell failure and leukemia in FA 14 . These findings are corroborated by human studies showing that dominant-negative ALDH2*2 variants in FA patients 15 and combined ADH5/ALDH2 deficiency both result in accelerated bone marrow failure and leukemia [16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

ALDH9A1 Deficiency as a Source of Endogenous DNA Damage that Requires Repair by the Fanconi Anemia Pathway

Jung

Ilyashov

Park

et al. 2022

Preprint

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Fanconi anemia (FA) pathway is required for the repair of DNA interstrand crosslinks (ICL). ICLs are caused by genotoxins, such as chemotherapeutic agents or reactive aldehydes. Inappropriately repaired ICLs contribute to hematopoietic stem cell (HSC) failure and tumorigenesis. While endogenous acetaldehyde and formaldehyde are known to induce HSC failure and leukemia in humans with FA, the effects of other toxic metabolites in FA pathogenesis have not been systematically investigated. Using a metabolism-focused CRISPR screen, we found that ALDH9A1 deficiency causes synthetic lethality in FA pathway-deficient cells. Combined deficiency of ALDH9A1 and FANCD2 causes genomic instability, apoptosis, and decreased hematopoietic colony formation. Fanca-/-Aldh9a1-/- mice exhibited an increased incidence of ovarian tumors. A suppressor CRISPR screen revealed that the loss of ATP13A3, a polyamine transporter, resulted in improved survival of FANCD2-/-ALDH9A1-/- cells. These findings implicate high intracellular polyamines and the resulting 3-aminopropanal or acrolein in the pathogenesis of FA. In addition, we find that ALDH9A1 variants may be modifying disease onset in FA patients.

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Genotoxic aldehydes in the hematopoietic system

Cited by 32 publications

References 111 publications

Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs

Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs

ALDH2 variance in disease and populations

ALDH9A1 Deficiency as a Source of Endogenous DNA Damage that Requires Repair by the Fanconi Anemia Pathway

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