Investigating clonal hematopoiesis in rhesus macaque and human
type: CreativeWork
description: Introduction Clonal hematopoiesis (CH) describes the expansion of blood cell output from one HSPC linked to an acquired somatic mutation conferring a competitive advantage. While clonality is a feature of hematological malignancies, recent large deep sequencing studies have revealed that clonally-expanded HSPC with specific somatic mutations are also prevalent in individuals without overt hematological abnormalities and become increasingly common with age. The phenomenon is thus termed age-related clonal hematopoiesis (ARCH). Individuals with CH are at greater risk for hematologic malignancies and cardiovascular diseases. However, predictive long-term preclinical animal models to recapitulate the spectrum of human CH are lacking. Such models would provide the opportunity to study parameters impacting the CH expansion and therapeutic options. CH expansions Furthermore, though CH has been shown to lead to hyperinflammation in murine models, its clinical implication in inflammatory disease such as COVID-19 has yet to be understood. Objectives 1. To examine the CH mutation landscape in blood cells from aged rhesus macaques (RMs) and to develop an autologous transplantation model of CH in RM to examine the impact of CH and potential therapeutic strategies long term. 2. To assess the impact of CH on COVID-19 disease severity in CH RM model and in human patients. 3. To study the competitive fitness of *RUNX1* mutant hematopoietic stem cells (HSPCs) in RM autologous transplant model. Results Through error-corrected sequencing of 56 human CH/myeloid malignancy genes, we identified natural CH driver mutations in aged RMs matching genes somatically mutated in human CH, with *DNMT3A* and *TET2* mutations being the most frequent. Of the 60 aged RM (median age of 25 years), 12 (20%) were to carry naturally occurring driver CH mutations and showed a trend of increasing with age. On the other hand, in the autologous transplantation RM model of CH, heterozygous *TET2* loss-of-functi…
abstract: Introduction Clonal hematopoiesis (CH) describes the expansion of blood cell output from one HSPC linked to an acquired somatic mutation conferring a competitive advantage. While clonality is a feature of hematological malignancies, recent large deep sequencing studies have revealed that clonally-expanded HSPC with specific somatic mutations are also prevalent in individuals without overt hematological abnormalities and become increasingly common with age. The phenomenon is thus termed age-related clonal hematopoiesis (ARCH). Individuals with CH are at greater risk for hematologic malignancies and cardiovascular diseases. However, predictive long-term preclinical animal models to recapitulate the spectrum of human CH are lacking. Such models would provide the opportunity to study parameters impacting the CH expansion and therapeutic options. CH expansions Furthermore, though CH has been shown to lead to hyperinflammation in murine models, its clinical implication in inflammatory disease such as COVID-19 has yet to be understood. Objectives 1. To examine the CH mutation landscape in blood cells from aged rhesus macaques (RMs) and to develop an autologous transplantation model of CH in RM to examine the impact of CH and potential therapeutic strategies long term. 2. To assess the impact of CH on COVID-19 disease severity in CH RM model and in human patients. 3. To study the competitive fitness of *RUNX1* mutant hematopoietic stem cells (HSPCs) in RM autologous transplant model. Results Through error-corrected sequencing of 56 human CH/myeloid malignancy genes, we identified natural CH driver mutations in aged RMs matching genes somatically mutated in human CH, with *DNMT3A* and *TET2* mutations being the most frequent. Of the 60 aged RM (median age of 25 years), 12 (20%) were to carry naturally occurring driver CH mutations and showed a trend of increasing with age. On the other hand, in the autologous transplantation RM model of CH, heterozygous *TET2* loss-of-functi…
author: Zhou, Yifan
language: eng
keywords: aging, clonal hematopoiesis, human, informatics, mutation, NGS, rhesus macaque
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c1cab164-655e-4ea8-acdd-eeacf134d011/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2024-02-04
date modified: 2026-07-22T22:24:04Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.112061