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Exp Hematol. 2019 Dec 12. pii: S0301-472X(19)31133-6. doi: 10.1016/j.exphem.2019.12.001. [Epub ahead of print]

Clonal hematopoiesis as a model for premalignant changes during aging.

Author information

1
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. Electronic address: david_steensma@dfci.harvard.edu.
2
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

Abstract

Over the course of the human life span, somatic DNA mutations accumulate in healthy tissues. This process has been most clearly described in blood and bone marrow, esophagus, colon, and skin, but cumulative DNA damage likely affects all tissues of the body. Although most acquired genetic variants have no discernable functional consequences, some randomly occurring somatic mutations confer a relative fitness advantage on a single stem cell and its progeny compared with surrounding cells, which may lead to progressive expansion of a clone (i.e., a genetically identical group of cells). When these mutations occur in a cell with the capacity to self-renew and expand, the mutations persist, and such clonal expansion is a risk factor for further mutation acquisition and clonal evolution. Hematopoietic stem cells are a special case of clonal expansion because both the stem cells and their blood cell progeny circulate in large numbers, and these cells are not subject to some of the anatomical restrictions that characterize other tissues in which somatic mutations conferring a fitness advantage also occur. Therefore, clonally restricted hematopoiesis can have biological and clinical consequences that are distinct from clonal expansions in other tissues. Such consequences include not only clonal progression to overt myeloid neoplasia (or, less commonly, to lymphoid neoplasia) driven by acquisition of secondary mutations in the cells of the expanded clone, but also cardiovascular events and, most likely, other diseases that are influenced by aberrant function of mutant blood cells. A more detailed understanding of how clonal hematopoiesis arises and how clonal selection and expansion occur, as well as development of strategies to avert the clinical consequences associated with clonal hematopoiesis, may both improve public health and yield more general insights into the biology of aging.

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