Macaque Age-Related Clonal Hematopoiesis Model Demonstrates Expansion of TET2-Disrupted Clones and Utility for Testing Therapeutic Approaches

Individuals with age-related clonal hematopoiesis (CH) are at greater risk for hematologic malignancies and cardiovascular diseases, however, there are no predictive preclinical animal models. We generated a rhesus macaque model via CRISPR/Cas9-mediated gene editing of hematopoietic stem and progenitor cells (HSPCs), followed by autologous transplantation. Long-term follow-up revealed reproducible and significant expansion of multiple HSPC clones with heterozygous TET2 loss-of-function mutations, compared to minimal expansion of clones bearing other mutations, suggesting a decrease in intrinsic TET2 activity is sufficient for CH. Blood counts were normal, but bone marrow of these animals were hypercellular and myeloid-predominant. Myeloid cells were hyperinflammatory with elevated interleukin (IL)-1β and IL-6. Blockade of IL-6 by tocilizumab reduced TET2 mutated allele frequency, suggesting that interruption of the IL-6 axis removes the selective advantage of mutant HSPCs. These findings provide a model for examining the pathophysiology of CH and testing of potential therapeutic interventions.