Precocious clonal hematopoiesis in Down syndrome is accompanied by immune dysregulation

Liggett, L. Alexander; Galbraith, Matthew D.; Smith, Keith P; Sullivan, Kelly D.; Granrath, Ross E; Enriquez-Estrada, Belinda; Kinning, Kohl T; Shaw, Jessica; Rachubinski, Angela L.; Espinosa, Joaquín M.; DeGregori, James

doi:10.1182/bloodadvances.2020003858

Cited by 14 publications

(5 citation statements)

References 21 publications

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“…It is also possible that the development of mutant clones requires a prolonged timeframe, beyond the typical lifespan of HGPS patients, even in conditions of accelerated aging and abnormal hematopoiesis. In agreement with our findings in HGPS children, absence of CHIP with VAF ≥ 2% was also revealed in deep sequencing studies of other young cohorts, including Down syndrome individuals and childhood cancer survivors [24,25], and only one mutation was identified by whole exome sequencing in a non-cancer cohort of 388 children [26]. These findings reinforce the relevance of time for the expansion of mutant clones that acquire a selective advantage, supporting the association of CHIP with chronological aging and emphasizing the differences between chronological aging (merely reflecting the time passed since birth) and biological aging (the decline over time in tissue and organismal function), which is exaggerated in HGPS patients.…”

Section: Abstract Somatic Mutations • Premature Aging Syndrome • Chip...supporting

confidence: 92%

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome

et al. 2022

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Clonal hematopoiesis of indeterminate potential (CHIP), defined as the presence of somatic mutations in cancer-related genes in blood cells in the absence of hematological cancer, has recently emerged as an important risk factor for several age-related conditions, especially cardiovascular disease. CHIP is strongly associated with normal aging, but its role in premature aging syndromes is unknown. Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare genetic condition driven by the accumulation of a truncated form of the lamin A protein called progerin. HGPS patients exhibit several features of accelerated aging and typically die from cardiovascular complications in their early teens. Previous studies have shown normal hematological parameters in HGPS patients, except for elevated platelets, and low levels of lamin A expression in hematopoietic cells relative to other cell types in solid tissues, but the prevalence of CHIP in HGPS remains unexplored. To investigate the potential role of CHIP in HGPS, we performed high-sensitivity targeted sequencing of CHIP-related genes in blood DNA samples from a cohort of 47 HGPS patients. As a control, the same sequencing strategy was applied to blood DNA samples from middle-aged and elderly individuals, expected to exhibit a biological age and cardiovascular risk profile similar to HGPS patients. We found that CHIP is not prevalent in HGPS patients, in marked contrast to our observations in individuals who age normally. Thus, our study unveils a major difference between HGPS and normal aging and provides conclusive evidence that CHIP is not frequent in HGPS and, therefore, is unlikely to contribute to the pathophysiology of this accelerated aging syndrome.

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Section: Abstract Somatic Mutations • Premature Aging Syndrome • Chip...supporting

confidence: 92%

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome

et al. 2022

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“…Individuals with T21 demonstrate presence of clonal haematopoiesis at higher frequency and younger age compared to disomic individuals. 7 Haematopoetic stem cells, differentiated lymphocytes and mononuclear cells from individuals with T21 display defective DNA repair mechanisms and increased sensitivity to oxidative damage, contributing to a state of genomic instability. 8 , 9 Increased expression of DYRK1A , located on chromosome 21, in haematopoietic cells caused significant derangement of DNA damage repair pathways in T21-derived induced pluripotent stem cell (iPSC) models, giving a possible mechanism for genome instability in T21.…”

Section: Role Of T21 In Leukaemogenesismentioning

confidence: 99%

“…10 , 11 In this way, T21 provides a microenvironment conducive to expansion of clonal populations and the acquisition of oncogenic mutations. 7 Single-cell studies have demonstrated increased mutagenesis in T21 foetal haematopoietic stem cells, leading to an increased risk of acquiring additional leukaemogenic mutations. 12 …”

Section: Role Of T21 In Leukaemogenesismentioning

confidence: 99%

Down syndrome-associated leukaemias: current evidence and challenges

Mason,

Cahill,

Diamond

et al. 2024

Therapeutic Advances in Hematology

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Children with Down syndrome (DS) are at increased risk of developing haematological malignancies, in particular acute megakaryoblastic leukaemia and acute lymphoblastic leukaemia. The microenvironment established by abnormal haematopoiesis driven by trisomy 21 is compounded by additional genetic and epigenetic changes that can drive leukaemogenesis in patients with DS. GATA-binding protein 1 ( GATA1) somatic mutations are implicated in the development of transient abnormal myelopoiesis and the progression to myeloid leukaemia of DS (ML-DS) and provide a model of the multi-step process of leukaemogenesis in DS. This review summarises key genetic drivers for the development of leukaemia in patients with DS, the biology and treatment of ML-DS and DS-associated acute lymphoblastic leukaemia, late effects of treatments for DS-leukaemias and the focus for future targeted therapy.

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“…RNA-seq was done as previously described ( 66 ). Briefly, peripheral blood was collected from human study participants in PAXgene RNA Tubes (PreAnalytiX/Qiagen, Cat# 762165).…”

Section: Supplementary Materials Formentioning

confidence: 99%

Interferon receptor gene dosage determines diverse hallmarks of Down syndrome

Waugh

Minter

Baxter

et al. 2022

Preprint

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Trisomy 21 causes Down syndrome, a condition characterized by cognitive impairments, immune dysregulation, and atypical morphogenesis. Using whole blood transcriptome analysis, we demonstrate that specific overexpression of four interferon receptors encoded on chromosome 21 associates with chronic interferon hyperactivity and systemic inflammation in Down syndrome. To define the contribution of interferon receptor overexpression to Down syndrome phenotypes, we used genome editing to correct interferon receptor gene dosage in mice carrying triplication of a large genomic region orthologous to human chromosome 21. Normalization of interferon receptor copy number attenuated lethal antiviral responses, prevented heart malformations, decreased developmental delays, improved cognition and normalized craniofacial anomalies. Therefore, interferon receptor gene dosage determines major hallmarks of Down syndrome, indicating that trisomy 21 elicits an interferonopathy amenable to therapeutic intervention.

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Precocious clonal hematopoiesis in Down syndrome is accompanied by immune dysregulation

Abstract: Key Points Children with Down syndrome develop early signs of clonal evolution that resemble traditional clonal hematopoiesis. Children with trisomy 21 who exhibit clonal hematopoiesis display cytokine and gene expression profiles indicative of disrupted immunity.

Cited by 14 publications

References 21 publications

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome

Down syndrome-associated leukaemias: current evidence and challenges

Interferon receptor gene dosage determines diverse hallmarks of Down syndrome

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