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Clonal hematopoiesis

TP53 clonal hematopoiesis promotes atherosclerosis

Nature Cardiovascular Research volume 2, pages 102–103 (2023)Cite this article

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Clonal hematopoiesis of indeterminate potential (CHIP) is a blood disorder that can increase the risk of cardiovascular disease. A new study reveals that CHIP driven by somatic mutations in DNA damage repair genes increases the risk of CVD in humans, and provides mechanistic insights in murine models.

Somatic mutations in hematopoietic stem cells (HSCs), like other somatic cells, are predicted to occur frequently1. These mutations uniquely impact the life of the HSCs; some enhance or inhibit the cells’ ability to divide and/or survive over time, and many mutations have no effect1. By the age of 50 almost everyone will have a detectable, albeit small, pool of circulating leukocytes carrying one or more mutations2. With time, mutated HSCs gain a competitive advantage and give rise to a condition termed clonal hematopoiesis of indeterminate potential (CHIP). People with CHIP are at an increased risk of overall mortality driven largely by cardiovascular disease (CVD) and hematological malignancies3. Two genes encoding proteins involved in regulating DNA methylation, DNMT3A and TET2, are the most prevalently mutated genes in CHIP, likely due to the open chromatin structure of HSCs and their reliance on DNA methylation for gene regulation4; other frequently mutated genes include ASXL1, JAK2 and the DNA damage repair (DDR) genes TP53 and PPM1D. It is established that DNMT3A, TET2, JAK2 and ASXL1 CHIP all increase the risk of atherosclerotic CVD; whether this elevated risk also exists for people carrying mutations in the DDR genes is unclear.

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Fig. 1: Trp53-driven CHIP accelerates atherosclerosis.

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Authors and Affiliations

  1. Department of Surgery, Ohio State University Wexner Medical Center, Columbus, OH, USA

    Prabhakara R. Nagareddy

  2. Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia

    Andrew J. Murphy

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  1. Prabhakara R. Nagareddy
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  2. Andrew J. Murphy
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Correspondence to Andrew J. Murphy.

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Nagareddy, P.R., Murphy, A.J. TP53 clonal hematopoiesis promotes atherosclerosis. Nat Cardiovasc Res 2, 102–103 (2023). https://doi.org/10.1038/s44161-022-00212-8

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