Clonal hematopoiesis of indeterminate potential and its impact on patient trajectories after stem cell transplantation

Park, Derek S.; Akuffo, Afua A.; Muench, David E.; Grimes, H. Leighton; Epling-Burnette, Pearlie K.; Maini, Philip K.; Anderson, Alexander R.A.; Bonsall, Michael B.

doi:10.1371/journal.pcbi.1006913

Cited by 21 publications

(14 citation statements)

References 65 publications

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“…However, these samples must be interpreted carefully as they may be contaminated with tumor tissue. In remission samples, it has already been described the presence of clonal hematopoiesis of indeterminate potential which is defined as the presence of recurrent somatic mutations in hematopoietic stem cells acquired throughout the life of the patients [41]. In saliva, the presence of a significant percentage of hematopoietic cells is conceivable, and, on the other side, the variant could have been acquired in a primary stem cell and be shared between myeloid and lymphoid lineages, so it could lead to a false positive if T cells are studied for validation [42].…”

Section: Discussionmentioning

confidence: 99%

Clinical utility of targeted next‐generation sequencing for the diagnosis of myeloid neoplasms with germline predisposition

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Clinical utility of targeted next‐generation sequencing for the diagnosis of myeloid neoplasms with germline predisposition

et al. 2021

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“…Previous studies have employed mathematical modeling to explore the parameters that underlie clonal expansions post-transplantation [29][30][31][32][33] . Here, we have explored potential mechanisms that can explain clonal elimination Fig.…”

Section: Discussionmentioning

confidence: 99%

A somatic evolutionary model of the dynamics of aneuploid cells during hematopoietic reconstitution

Rozhok

Silberman

Higa

et al. 2020

Sci Rep

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Aneuploidy is a feature of many cancers. Recent studies demonstrate that in the hematopoietic stem and progenitor cell (HSPC) compartment aneuploid cells have reduced fitness and are efficiently purged from the bone marrow. However, early phases of hematopoietic reconstitution following bone marrow transplantation provide a window of opportunity whereby aneuploid cells rise in frequency, only to decline to basal levels thereafter. Here we demonstrate by Monte carlo modeling that two mechanisms could underlie this aneuploidy peak: rapid expansion of the engrafted HSpc population and bone marrow microenvironment degradation caused by pre-transplantation radiation treatment. Both mechanisms reduce the strength of purifying selection acting in early post-transplantation bone marrow. We explore the contribution of other factors such as alterations in cell division rates that affect the strength of purifying selection, the balance of drift and selection imposed by the HSPC population size, and the mutation-selection balance dependent on the rate of aneuploidy generation per cell division. We propose a somatic evolutionary model for the dynamics of cells with aneuploidy or other fitness-reducing mutations during hematopoietic reconstitution following bone marrow transplantation. Similar alterations in the strength of purifying selection during cancer development could help explain the paradox of aneuploidy abundance in tumors despite somatic fitness costs. Aneuploidy, or deviation of the chromosome number from the normal karyotype (resulting from chromosome mis-segregation), is associated with many cancers, being prevalent in both solid cancers and leukemia 1-4. The effects of aneuploidy vary, with some cellular phenotypes dependent on what specific chromosome(s) is lost or gained, and other phenotypes arising from a general stress response to aneuploidy 5. Consequently, associations of aneuploidy with cancers range widely, from a few percent, such as the loss of chromosome 1 or gain of chromosome 5 in kidney adenocarcinoma, to 50%, such as the loss of chromosome 3 in melanoma, and even 70% for the loss of chromosome 22 in meningiomas 2. In total, almost 90% of cancers exhibit gains or losses of at least one chromosome arm, with patterns specific to particular tumor types 4. For example, squamous cell cancers originating in multiple organs exhibit a common pattern of chromosome arm 3p loss and 3q gain. Aneuploid cells have been shown to drive adaptation in yeast 6-8. This evidence has led to speculations that by conferring greater adaptability, variability of chromosomal ploidy in a cell population might lead to the expansion of aneuploid clones in human tissues, fueling further accumulation of oncogenic alterations in cells and progression to cancer 9-11. However, aneuploidy has been shown to more commonly reduce the fitness of animal

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“…Several studies have investigated the impact of clonal haematopoiesis on the outcome of HSC transplantation therapy ( Frick et al, 2019 ; Gibson et al, 2017 ; Mouhieddine et al, 2020 ; Ortmann et al, 2019 ). However, the implications of clonal haematopoiesis for stem cell transplantation are difficult to identify owing to the high degree of mutational heterogeneity present within the genetically distinct subclones ( Park et al, 2019 ). Therefore, studying it at single-cell resolution can significantly improve our understanding of the process.…”

Section: Hsc Transplantation At Single-cell Resolutionmentioning

confidence: 99%

Haematopoietic ageing through the lens of single-cell technologies

Strzelecka

Damm

2021

Disease Models &Amp; Mechanisms

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Human lifespan is now longer than ever and, as a result, modern society is getting older. Despite that, the detailed mechanisms behind the ageing process and its impact on various tissues and organs remain obscure. In general, changes in DNA, RNA and protein structure throughout life impair their function. Haematopoietic ageing refers to the age-related changes affecting a haematopoietic system. Aged blood cells display different functional aberrations depending on their cell type, which might lead to the development of haematologic disorders, including leukaemias, anaemia or declining immunity. In contrast to traditional bulk assays, which are not suitable to dissect cell-to-cell variation, single-cell-level analysis provides unprecedented insight into the dynamics of age-associated changes in blood. In this Review, we summarise recent studies that dissect haematopoietic ageing at the single-cell level. We discuss what cellular changes occur during haematopoietic ageing at the genomic, transcriptomic, epigenomic and metabolomic level, and provide an overview of the benefits of investigating those changes with single-cell precision. We conclude by considering the potential clinical applications of single-cell techniques in geriatric haematology, focusing on the impact on haematopoietic stem cell transplantation in the elderly and infection studies, including recent COVID-19 research.

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Clonal hematopoiesis of indeterminate potential and its impact on patient trajectories after stem cell transplantation

Cited by 21 publications

References 65 publications

Clinical utility of targeted next‐generation sequencing for the diagnosis of myeloid neoplasms with germline predisposition

Clinical utility of targeted next‐generation sequencing for the diagnosis of myeloid neoplasms with germline predisposition

A somatic evolutionary model of the dynamics of aneuploid cells during hematopoietic reconstitution

Haematopoietic ageing through the lens of single-cell technologies

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