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Macaque Age-Related Clonal Hematopoiesis Model Demonstrates Expansion of TET2-Disrupted Clones and Utility for Testing Therapeutic Approaches
65 Pages Posted: 29 Apr 2020 Publication Status: Review Complete
More...Abstract
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.
Keywords: age-related clonal hematopoiesis, clonal hematopoiesis of indeterminate potential, hematopoietic stem and progenitor cells, clonal expansion, rhesus macaque, non-human primate model, CRISPR/Cas9, NLRP3 inflammasome, interleukin-6, tocilizumab
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