Genetic Resistance to Leukemia

Unlike genetic mutations that are inherited directly from parents, somatic mutations are changes in the DNA that occur over a singular lifetime and accumulate. All the tissues in body are created and maintained by particular stem cells or progenitor cells. When mutations occur in stem cells or progenitor cells that give a survival advantage over the unmutated variety, they can grow via clonal expansion. The mechanism(s) of such expansion (clonal hematopoiesis) have been identified; however, the factors that may contribute to delaying this cell growth is poorly understood. Uncontrolled clonal expansion in hematopoietic stem cells or progenitors may lead to leukemia.

Human Leukemic White Blood Cells

In a recent article in the journal, Science, Agarwal et al. have studied and reported on an inheritable genetic variant that seems to protect against clonal hematopoiesis and its possible progression to leukemia.

According to the investigators in this study, “The focus of clonal expansion studies, which have led to the identification of aging-associated clonal hematopoiesis of indeterminate potential (CHIP). CHIP is defined by the presence of somatic mutations in at least one gene associated with cancer in white blood cells (the most frequently mutated genes being DNA methyltransferase 3 a, or DNMT3A; tet methylcytosine dioxygenase 2, or TED; and ASXL transcriptional regulator 1, or ASXLI), with a proportion of cancer-associated variant copies of a gene (variant allele frequency) of at least 2% in blood and bone marrow cells, and in the absence of another blood disorder. Most CHIP mutations give a competitive advantage to hematopoietic stem cells (HSCs) over normal HSCs, particularly in eroded and aged hematopoietic systems exposed to inflammation (2). The size of the mutant clone population is a major predictor of poor outcomes in CHIP carriers (3). In particular, CHIP is associated with a 10- to 12-fold increased risk of developing myeloid malignancy (4), a group of blood cancers. Notably, mutant HSC populations can stagnate and even shrink in an individual over a long period of time (5). Environmentally inherited factors that prevent or slow mutant clonal expansion may explain these variations.”

The researchers involved in this study went on to further elucidate the mechanism as described above. These data are exceedingly valuable in that they may ultimately lead to an effective diagnostic tool to more accurately identify the risk factors for age-associated clonal hematopoiesis.

Alcohol, Acetaldehyde and Cancer

It has long been understood that excessive drinking of alcohol can lead to serious impairments in various organs including the liver and brain.   However, it is now become clear that there is a real risk associated with chronic consumption of alcohol(ethanol) with increased risk of getting certain kinds of cancers including upper aerodigestive tract, the liver, the large intestine and the female breast.

In a recent paper that appeared in the journal Science, the etiology of this relationship has been demonstrated.  Multiple mechanisms have been elaborated to explain this relationship.  According to the authors, “Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest.

Structure of Acetaldehyde – Black – Carbon; White – Hydrogen; Red - Oxygen

“AA is toxic, mutagenic and carcinogenic in animal experiments.  AA binds to DNA and forms carcinogenic adducts.  Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics.  Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk.  Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form.  This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol.  When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted.  In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2.  In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast.  These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis.”

This article elaborated further,” Acetaldehyde is highly toxic, mutagenic and carcinogenic.  AA interferes at many sites with DNA synthesis and repair and can, consequently, result in tumor development [6, 7].  Numerous in vitro and in vivo experiments in prokaryotic and eukaryotic cell cultures as well as in animal models have shown that AA has direct mutagenic and carcinogenic effects.”

In conclusion, these data strongly reinforce the nature of the  relationship between the chronic drinking of ethanol and certain cancers.