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

被引：20

作者：

Shin, Tae-Hoon ^{[1
,2
]}

Zhou, Yifan ^{[1
,3
,4
]}

Chen, Shirley ^{[1
]}

Cordes, Stefan ^{[1
]}

Grice, Max Z. ^{[1
]}

Fan, Xing ^{[1
]}

Lee, Byung-Chul ^{[1
]}

Aljanahi, Aisha A. ^{[1
]}

Hong, So Gun ^{[1
]}

Vaughan, Kelli L. ^{[5
]}

Mattison, Julie A. ^{[5
]}

Kohama, Steven G. ^{[6
]}

Fabre, Margarete A. ^{[3
,4
]}

Uchida, Naoya ^{[7
]}

Demirci, Selami ^{[7
]}

Corat, Marcus A. F. ^{[1
,8
]}

Metais, Jean-Yves ^{[1
,9
]}

Calvo, Katherine R. ^{[10
]}

Buscarlet, Manuel ^{[11
]}

Natanson, Hannah ^{[1
]}

McGraw, Kathy L. ^{[12
]}

List, Alan F. ^{[13
]}

Busque, Lambert ^{[11
]}

Tisdale, John F. ^{[7
]}

Vassiliou, George S. ^{[3
,4
]}

Yu, Kyung-Rok ^{[1
,14
,15
]}

Dunbar, Cynthia E. ^{[1
]}

机构：

[1] NHLBI, Translat Stem Cell Biol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA

[2] Jeju Natl Univ, Coll Vet Med, Dept Lab Anim Med, Jeju, South Korea

[3] Wellcome Trust Sanger Inst, Haematol Canc Genet, Cambridge, England

[4] Univ Cambridge, Wellcome Med Res Council MRC, Cambridge Stem Cell Inst, Cambridge, England

[5] NIA, Translat Gerontol Branch, NIH Anim Ctr, Dickerson, MD USA

[6] Oregon Hlth & Sci Univ, Div Neurosci, Oregon Natl Primate Res Ctr, Beaverton, OR USA

[7] NHLBI, Cellular & Mol Therapeut Branch, NIH, Bldg 10, Bethesda, MD 20892 USA

[8] Univ Estadual Campinas, Multidisciplinary Ctr Biol Res, Campinas, Brazil

[9] St Jude Childrens Res Hosp, Dept Bone Marrow Transplantat & Cellular Therapy, 332 N Lauderdale St, Memphis, TN 38105 USA

[10] NIH, Hematol Sect, Dept Lab Med, Clin Ctr, Bldg 10, Bethesda, MD 20892 USA

[11] Univ Montreal, Hop Maisonneuve Rosemont, Montreal, PQ, Canada

[12] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[13] Precis Biosci Inc, Durham, NC USA

[14] Seoul Natl Univ, Dept Agr Biotechnol, Seoul, South Korea

[15] Seoul Natl Univ, Res Inst Agr & Life Sci, Seoul, South Korea

来源：

BLOOD | 2022年 / 140卷 / 16期

基金：

美国国家卫生研究院; 英国惠康基金; 新加坡国家研究基金会; 英国医学研究理事会;

关键词：

STEM-CELLS; MUTATIONS; DNMT3A; CANCER; 5-METHYLCYTOSINE; INHIBITION; DRIVER; COMMON; RISK;

D O I：

10.1182/blood.2021014875

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-1 beta (IL-1 beta) 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.

引用

页码：1774 / 1789

页数：16