Clonal hematopoiesis of indeterminate potential (CHIP) is arguably the most studied form of somatic mosaicism, in which stem cells accumulate mutations over time, and thus patterns of those mutations spread out into the tissue supported by those stem cells. In this case, the “tissue” is the immune system, made up of immune cells descended from the hematopoietic stem cell population that is resident in the bone marrow. There is evidence for CHIP to contribute to forms of age-related disease and aspects of aging more generally, which is an argument for somatic mosaicism in all tissues to contribute to degenerative aging.
Aging is associated with organ and tissue function deterioration and consequent increased risk of disease occurrence and mortality. Recent scientific advancements have succeeded in increasing the human life span and attempts are being made to enhance the longevity further. This stretched longevity exposes the organism to increased cellular stress and accumulation of DNA damage. Mutations in leukemia-associated driver oncogenes like DNMT3A, TET2, ASXL1, TP53, PPM1D, SF3B1, SRSF2, and IDH1/IDH2, provide selective growth advantage to the mutated clones over normal hematopoietic stem cells (HSCs). Altered bone marrow (BM) microenvironment and increased pro-inflammatory milieu further accelerates the clonal expansion and eventually reduces the hematopoietic heterogeneity.
Significant increase in clonal hematopoiesis with more than two percent of peripheral blood cells arising from single hematopoietic clone is termed as clonal hematopoiesis of indeterminate potential (CHIP). CHIP is increasingly recognized as an age-associated risk factor linked to cardiovascular and neurological disorders. While epidemiological and experimental studies suggest mechanistic involvement of inflammation, current human evidence primarily supports risk association rather than definitive causality, which may vary across mutation types. Here, we have discussed the intrinsic and extrinsic changes occurring in the hematopoietic system and its role in enhancing the clonal expansion during aging. We have further discussed the role of CHIP in various diseases and diagnostic tools being currently used for CHIP diagnosis. Finally, we also discuss the current CHIP management strategies and global status of CHIP related research.
