# Hematopoietic stem cell aging promotes TET2 clonal hematopoiesis

## TL;DR

Aging hematopoietic stem cells become less fit, allowing mutated cells to expand more easily, leading to clonal hematopoiesis.

## Contribution

The study reveals that aging reduces the fitness of healthy hematopoietic stem cells, promoting clonal expansion of Tet2-mutant cells.

## Key findings

- Old donor Tet2 KO hematopoietic stem cells expand faster than young ones in a mouse model of clonal hematopoiesis.
- Aged hematopoietic stem cells show enhanced RUNX1 activation and ribosomal protein gene expression, inducing a p53-mediated stress response.
- Tet2 inactivation abrogates aging-related changes in hematopoietic stem cells, linking these changes to clonal hematopoiesis.

## Abstract

Aging is strongly associated with the incidence of clonal hematopoiesis (CH) and myeloid malignancies. However, the role of aging in the clonal selection for CH mutations is not well understood. In a mouse model of CH, we observe that transplanted Tet2 KO hematopoietic stem cells (HSC) from old donor mice expand at a faster rate than young irrespective of the age of the recipient mice; that this acceleration is observed by middle age; and that it is primarily due to the aging-associated reduction in fitness of aged competitor non-mutant HSC. Mechanistically, in both mice and humans, we found that aged HSC exhibit enhanced activation of a RUNX1 transcriptional program and increased expression of ribosomal protein genes inducing a p53-mediated stress response, and that these changes are abrogated by Tet2/TET2 inactivation. Thus, aging creates the conditions that foster clonal expansion of Tet2, Runx1 and Trp53 mutant HSC promoting CH.