- PhD, Biochemisty, University of California, Berkeley
Biochemistry, Cardiovascular Biology, Metabolism
Clonal hematopoiesis: A new mechanism of cardiovascular disease
Hematopoietic stem cells produce multiple blood cell types and replenish themselves through a self-renewal process. As with all cells, hematopoietic stem cells accumulate somatic mutations with age. While most mutations have little or no effect on cellular fitness, some mutations will occur in “driver” genes that enable their positive selection. Thus, the mutant cells can outcompete neighboring wild-type cells leading to a clonal expansion. Notably, these mutant hematopoietic stem cell clones give rise to progeny immune cells that harbor the same mutant allele, and it has been shown that these mutations can functionally corrupt the circulating immune cell pool. Clonal expansions in blood cells have been found to occur in relatively healthy individuals who lack overt signs of blood cancer. This pre-cancerous condition has historically been referred to as “clonal hematopoiesis” and more recently as “clonal hematopoiesis of indeterminate potential” or “age-related clonal hematopoiesis” to distinguish it from the clonal expansions that occur in malignant blood disorders.
Clonal hematopoiesis is partcularly prevalent in the elderly where clone size can become relatively large (>20% of an individual’s white blood cells can be derived from a single clone). While clonal hematopoiesis had long been viewed as a benign feature of the aging process, recent studies have shown that it is associated with mortality due in large part to elevated cardiovascular disease risk. Studies in experimental systems have provided evidence that clonal hematopoiesis can contribute to the development of age-related diseases including atherosclerosis, heart failure and insulin resistance. Collective epidemiological and experimental studies indicate that clonal hematopoiesis is a newly recognized causal risk factor for cardiovascular disease that is as prevalent and consequential as the traditional risk factors (hyperlipidemia, hypertension, smoking and diabetes) that have been recognized for decades. Details of this new disease mechanism are being uncovered, and these findings could facilitate the development of precision medicine strategies that are tailored to account for the diverse clonal hematopoiesis patterns between individuals.
In addition to the age-related clonal hematopoiesis described above, there is a more aggressive form of this condition that is referred to as “therapy-associated clonal hematopoeisis”. This occurs in individuals who have been treated for cancer, and it is associated with clones that arise from mutations in DNA damage-response pathway genes that confer cellular resistance to the genotoxic stress of the cancer therapy. Recent experimental studies suggest that therapy-related clonal hematopoiesis can contribute to the medium- and long-term toxicity of anticancer agents on the heart, and this mechanism may contribute to the prevalent cardiovascular disorders that are observed in cancer survivors.
The field of clonal hematopoiesis is in its infancy. There is an incomplete understanding of the mechanisms that give rise to clonal expansions in hematopoietic cells and the health consequences of these events. The known driver genes comprise a diverse group of regulatory molecules, and it is likely that they play divergent roles in disease processes. It is also reasonable to speculate that driver genes will exhibit disease-specific actions and likely impact age-related diseases beyond the cardiovascular system. Given the large number of driver gene candidates, studies require methodologies that are far more expansive in scope than the typical “single gene/single disease” approach. In view of these considerations, it is increasingly appreciated that the currently known pool of driver genes can only account for a portion of the clonal hematopoiesis events observed in individuals. The mechanisms that give rise to these enigmatic clones are poorly understood, yet epidemiological studies indicate that they are also associated with increased mortality. Thus, there are major unaddressed challenges and ample opportunities for new investigators to make progress in this rapidly expanding area of medical research.