Bone marrow stem cells are extremely sensitive to the primary by-product of alcohol, which causes permanent damage to their DNA claims researchers from the Medical Research Council (MRC) Lab of Molecular Biology.

The research, which was conducted on mice, uncovers two mechanisms that normally control this type of damage; a protein group that recognizes and repairs DNA damage and an enzyme that eliminates acetaldehyde, alcohol’s toxic breakdown product.

Mice lacking both protective mechanisms developed bone marrow failure stemming from blood stem cell damage.
These results mark the first time that scientists have been able to explain why bone marrow fails in Fanconi anemia (FA) patients. FA is a rare genetic disorder.

The report concludes that FA turns off the bone marrow’s “repair kit” via FA gene mutation which causers DNA damage from acetaldehyde to continue unchecked. This damage is responsible for bone marrow failure and developmental defects in FA patients and makes them especially vulnerable to blood and other types of cancer.

These findings may have particular significance for the world’s Asian population, many of whom suffer from “Asian flush syndrome”. People with AFS lack the enzyme ALDH2 and therefore could be particularly susceptible to DNA damage. The authors warned that this subset of the Asian population could suffer permanent DNA damage with alcohol consumption and be more highly prone to blood cancer, bone marrow failure and premature aging than the Asian population at-large.

“Blood stem cells are responsible for providing a continuous supply of healthy blood cells throughout our lifespan. With age, these vital stem cells become less effective because of the build up of damaged DNA. Our study identifies a key source of this DNA damage and defines two protective mechanisms that stem cells use to counteract this threat. Last year we published a paper showing that without this two-tier protection, alcohol breakdown products are extremely toxic to the blood. We now identify exactly where this DNA damage is occurring, which is important because it means that alcohol doesn’t just kill off healthy circulating cells, it gradually destroys the blood cell factory. Once these blood stem cells are damaged they may give rise to leukaemias and when they are gone they cannot be replaced, resulting in bone marrow failure,” Dr KJ Patel, who is the primary investigator.

“The findings may be particularly significant for a vast number of people from Asian countries such as China, where up to a third of the population are deficient in the ALDH2 enzyme. Alcohol consumption in these individuals could overload their FA DNA repair kit causing irreversible damage to their blood stem cells. The long-term consequences of this could be bone marrow dysfunction and the emergence of blood cancers,” Patel added.

“This study provides much sought-after explanation of the biology underpinning the devastating childhood disease Fanconi anemia. In future this work may underpin new treatments for this genetic disease, which currently is associated with a very poor prognosis. It also helps to inform large numbers of the global population, who are deficient in the ALDH2 enzyme, that drinking alcohol may be inflicting invisible damage on their DNA,” commented Sir Hugh Pelham, director of the MRC Laboratory of Molecular Biology.