Rhesus Macaques As Natural Models for Age-Related Clonal Hematopoiesis

Clonal hematopoiesis (CH) describes the clonal expansion of blood cells derived from hematopoietic stem/progenitor cell (HSPC) sharing the same somatic mutations. Recent large deep sequencing studies revealed that CH somatic mutations are prevalent in peripheral blood cells of individuals without overt hematological abnormalities and become increasingly common and larger in clone size with age. While the risk of eventual progression to hematologic abnormalities or leukemia appears to be higher in individuals with CH, the parameters impacting on progression are unclear. In addition, CH confers a greater risk for cardiovascular disease (CVD) and possibly other systemic diseases. However, commonly used experimental animals such as mice do not develop CH and there is a lack of natural in vivo model organisms to investigate the mechanisms underlying CH development and malignant progression. We addressed this unmet need via the investigation of the rhesus macaque (RM) as a potential model organism for CH given the close phylogenetic relationship to humans and the associated comparable HSPC frequencies, replication times, telomere lengths and bone marrow environments. We assessed the incidence and variant allele frequency (VAF) of CH somatic mutations in 35 aged RM (median age 27) by error-corrected targeted ultra-deep sequencing of the exons from the top 56 human CH genes. We identified 12 animals (median age 30) carrying at least one nonsynonymous somatic mutation in CH genes on this panel with a VAF between 0.5% to 11.4%. Furthermore, in one animal where longitudinal samples were available, we observed a gradual expansion of a one-base pair deletion in DNMT3A across multiple cell-lineage as a function of age. All animals showed normal complete blood counts and were without overt hematological malignancies. While we continue to expand our study cohort, data so far suggest that RM is a natural model for CH.