CHIP: a clonal odyssey of the bone marrow niche
Wolfgang E. Schleicher, … , James DeGregori, Eric M. Pietras
Wolfgang E. Schleicher, … , James DeGregori, Eric M. Pietras
Published August 1, 2024
Citation Information: J Clin Invest. 2024;134(15):e180068. https://doi.org/10.1172/JCI180068.
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Review Series

CHIP: a clonal odyssey of the bone marrow niche

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the selective expansion of hematopoietic stem and progenitor cells (HSPCs) carrying somatic mutations. While CHIP is typically asymptomatic, it has garnered substantial attention due to its association with the pathogenesis of multiple disease conditions, including cardiovascular disease (CVD) and hematological malignancies. In this Review, we will discuss seminal and recent studies that have advanced our understanding of mechanisms that drive selection for mutant HSPCs in the BM niche. Next, we will address recent studies evaluating potential relationships between the clonal dynamics of CHIP and hematopoietic development across the lifespan. Next, we will examine the roles of systemic factors that can influence hematopoietic stem cell (HSC) fitness, including inflammation, and exposures to cytotoxic agents in driving selection for CHIP clones. Furthermore, we will consider how — through their impact on the BM niche — lifestyle factors, including diet, exercise, and psychosocial stressors, might contribute to the process of somatic evolution in the BM that culminates in CHIP. Finally, we will review the role of old age as a major driver of selection in CHIP.

Authors

Wolfgang E. Schleicher, Bridget Hoag, Marco De Dominici, James DeGregori, Eric M. Pietras

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Figure 2

A model of an inflammatory feed-forward cycle in CHIP.

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A model of an inflammatory feed-forward cycle in CHIP. Tet2 deficiency l...
Tet2 deficiency leads to myeloid skewing and an increase in the number of mature myeloid cells carrying the mutation, in the BM and elsewhere. Because TET2 regulates inflammatory gene expression, its loss in myeloid cells leads to a hyperinflammatory BM niche, driven by elevated IL-1 and TNF-α signaling. This, in turn, has been shown to further promote Tet2–/– clonal expansion. Thus, Tet2-mutant HSPCs may establish conditions in the BM that favor their own expansion, effectively creating a feed-forward loop. This model may be relevant to other common CHIP mutations that demonstrate selective advantages under inflammatory stress.