January 3, 2018

expert reaction to a mechanism in mice for blood stem cell damage from alcohol

Publishing in Nature, researchers have reported that a metabolite of alcohol, acetaldehyde, causes damage to the DNA of blood-forming stem cells, in a mouse model.

Prof. Robin Lovell-Badge FMedSci FRS, Group Leader at the Francis Crick Institute, said:

“This is an important study revealing mechanisms of DNA damage and repair due to high levels of aldehydes and how this can cause cancer involving blood stem cells. It is particularly relevant to individuals deficient in the enzymes that normally eliminate aldehydes, which are derived from normal cellular processes as well as from alcohol. Drinking excessively is bad for us in several ways, and can eventually lead to other types of cancer, notably of the liver. However, the work shows that most of us are protected from the effects of aldehydes, at least the blood stem cells, not only by these enzymes, but also by other mechanisms that reduce the likelihood of DNA damage, or of cells containing this, to persist.”

Some further explanation:

“DNA damage leads to cell death, if unchecked, but it also triggers mechanisms that act to repair the broken DNA, allowing the cells to survive. However, if the DNA is repaired incorrectly this can lead to cancer. Aldehydes, formed naturally through enzymatic processes in the body, and notably as derivatives of alcohol, are known to promote DNA damage when they occur at high levels. For example, liver cancer can be a consequence of high alcohol intake due to the DNA damaging effects of aldehydes. However, high levels of aldehydes can also result from deficiencies in the enzymes that normally eliminate them, aldehyde dehydrogenases. This can be associated with cancer of the oesophagus, or, as is shown in this paper, to malignancies affecting blood cells, where the type of cancer seems to relate to how well the different DNA repair mechanisms operate.

“The authors show in mice that mutations in both the aldh2 gene, which encodes for aldehyde dehydrogenase, and Fancd2, a gene whose product is required to repair DNA that has been cross-linked, leads to accumulation of DNA damage in blood stem cells, especially if p53, a protein involved in eliminating damaged cells, is also mutated. The pattern and degree of DNA instability occurring in individual stem cells was analysed by transplanting them into other mice, where their ability to multiply and reconstitute haematopoiesis, the formation of all the different blood cell types, could also be assessed. This allowed the authors to determine which DNA repair pathways are protective and which are not.”

Prof. Magdalena Zernicka-Goetz, Professor of Mammalian Development and Stem Cell Biology at the University of Cambridge, said:

“This is beautiful work which puts our finger on the molecular basis for the link between alcohol and increased cancer risk and stem cells. Very important.”

Prof. Malcolm Alison, Professor of Stem Cell Biology at the Barts Cancer Institute, Queen Mary University of London, said:

“Drinkers beware: most of our organs and tissues have stem cells, immortal cells that replenish cells lost through the likes of old age throughout our lives, and the haematopoietic system is no exception.

“Many people believe that most cancers arise in stem cells, for these cells are already equipped with many of the tools required for longevity. This new study from Cambridge now finds that mouse haematopoietic stem cells can be mutated by a metabolite of alcohol, acetaldehyde. Moreover damage was exacerbated by knocking out a protective enzyme called aldehyde dehydrogenase 2 (ALDH2), an enzyme protecting us from a potentially toxic build-up of acetaldehyde.

“There may be implications for other cancers; 8% of the world’s population, largely of East Asian ancestry, have an inherited deficiency in ALDH2 and this could be a contributory factor for the extremely high prevalence of oesophageal cancers in countries such as China.”

 * ‘Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells’ by Juan I. Garaycoechea et al. was published in Nature  on Wednesday 3^rd January 2018. 

Declared interests

None received.