A macaque clonal hematopoiesis model demonstrates expansion of TET2-disrupted clones and utility for testing interventions

生物 造血 髓样 恒河猴 祖细胞 移植 癌症研究 免疫学 清脆的 基因 遗传学 干细胞 内科学 医学
作者
Tae–Hoon Shin,Yifan Zhou,Shirley Chen,Stefan Cordes,Max Z. Grice,Xing Fan,Byung‐Chul Lee,Aisha AlJanahi,So Gun Hong,Kelli L. Vaughan,Julie A. Mattison,Steven G. Kohama,Margarete A. Fabre,Naoya Uchida,Selami Demirci,Marcus Alexandre Finzi Corat,Jean‐Yves Métais,Katherine R. Calvo,Manuel Buscarlet,Hannah Natanson,Kathy L. McGraw,Alan F. List,Lambert Busque,John F. Tisdale,George S. Vassiliou,Kyung‐Rok Yu,Cynthia E. Dunbar
出处
期刊:Blood [American Society of Hematology]
卷期号:140 (16): 1774-1789 被引量:19
标识
DOI:10.1182/blood.2021014875
摘要

Abstract Individuals with age-related clonal hematopoiesis (CH) are at greater risk for hematologic malignancies and cardiovascular diseases. However, predictive preclinical animal models to recapitulate the spectrum of human CH are lacking. Through error-corrected sequencing of 56 human CH/myeloid malignancy genes, we identified natural CH driver mutations in aged rhesus macaques matching genes somatically mutated in human CH, with DNMT3A mutations being the most frequent. A CH model in young adult macaques was generated via autologous transplantation of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9–mediated gene-edited hematopoietic stem and progenitor cells (HSPCs), targeting the top human CH genes with loss-of-function (LOF) mutations. Long-term follow-up revealed reproducible and significant expansion of multiple HSPC clones with heterozygous TET2 LOF mutations, compared with minimal expansion of clones bearing other mutations. Although the blood counts of these CH macaques were normal, their bone marrows were hypercellular and myeloid-predominant. TET2-disrupted myeloid colony-forming units isolated from these animals showed a distinct hyperinflammatory gene expression profile compared with wild type. In addition, mature macrophages purified from the CH macaques showed elevated NLRP3 inflammasome activity and increased interleukin-1β (IL-1β) and IL-6 production. The model was used to test the impact of IL-6 blockage by tocilizumab, documenting a slowing of TET2-mutated expansion, suggesting that interruption of the IL-6 axis may remove the selective advantage of mutant HSPCs. These findings provide a model for examining the pathophysiology of CH and give insights into potential therapeutic interventions.
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