Clinical consequences of clonal hematopoiesis of indeterminate potential

Abstract

Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones.

Figure 1.

Probable mechanism of cardiovascular injury associated with clonal hematopoiesis. Mutant HSC-derived monocytes circulate and are recruited to plaques in arteries. There, they differentiate into tissue macrophages, which promote inflammation. The inflammasome activates IL-1β, which, in turn, promotes local inflammation, accelerating atherosclerosis, as well as induces expression of the P-selectin glycoprotein, which, in turn, recruits more monocytes (clonally derived and wild-type). Clonally derived platelets may also play an important role. In addition, increased interleukin-1β secretion in endothelial cells within the myocardium promotes disordered remodeling that potentiates heart failure.