60 Years of clonal hematopoiesis research: From X-chromosome inactivation studies to the identification of driver mutations

Ayachi, Sami; Buscarlet, Manuel; Busque, Lambert

doi:10.1016/j.exphem.2020.01.008

Cited by 26 publications

(22 citation statements)

References 99 publications

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“…Age-related accumulation and clonal expansion of cancer-associated somatic mutations in healthy tissues has been posited recently as a pre-malignant status consistent with the multistage model of carcinogenesis (Martincorena, 2019). However, the widespread presence of cancer-associated mutations in healthy tissues highlights the complexity of early detection and diagnosis of cancer (Ayachi et al, 2020; Genovese et al, 2014; Jaiswal et al, 2014; Lee-Six et al, 2019; Martincorena et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Clonal haematopoiesis of indeterminate potential (CHIP) is defined as the clonal expansion of haematopoietic stem and progenitor cells (HSPCs) in healthy aged individuals. CHIP affects more than 10% of individuals over the age of 60 years and is associated with an estimated 10-fold increased risk for the later onset of haematological neoplasms (Ayachi et al, 2020; Genovese et al, 2014; Jaiswal et al, 2014). There is a clear benefit of detecting CHIP early as the association between clone size and malignancy progression is well-established (Jaiswal and Ebert, 2019; Jaiswal et al, 2014; Park and Bejar, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

Latorre-Crespo

Terradas-Terradas

et al. 2021

Preprint

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The prevalence of clonal haematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. Since mutations in stem cells often drive leukaemia, we hypothesised that stem cell fitness substantially contributes to transformation from CHIP to leukaemia. Stem cell fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. We set out to quantify the fitness effects of CHIP drivers over a 15 year timespan in older age, using longitudinal error-corrected sequencing data. It is currently unknown whether mutations in different CHIP genes lead to distinct fitness advantages that could form the basis for patient stratification. We developed a new method based on drift-induced fluctuation (DIF) filtering to extract fitness effects from longitudinal data, and thus quantify the growth potential of variants within each individual. Our approach discriminates naturally drifting populations of cells and faster growing clones, while taking into account individual mutational context. We show that gene-specific fitness differences can outweigh inter-individual variation and therefore could form the basis for personalised clinical management.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

Latorre-Crespo

Terradas-Terradas

et al. 2021

Preprint

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“…As clonal hematopoiesis is covered in other articles in this collection [2,3,6], we focus this review on recent studies that have used whole-genome sequencing to track clonal dynamics in unperturbed human hematopoiesis and touch upon future applications of the approach in studying how aberrations in clonal dynamics are evidenced in disease.…”

mentioning

confidence: 99%

Tracking hematopoietic stem cells and their progeny using whole-genome sequencing

Lee-Six

Kent

2020

Experimental Hematology

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Despite decades of progress in our understanding of hematopoiesis through the study of animal models and transplantation in humans, investigating physiological human hematopoiesis directly has remained challenging. Questions on the clonal structure of the human hematopoietic stem cell (HSC) pool, such as "how many HSCs are there?" and "do all HSC clones actively produce all blood cell types in equal proportions?" remain open. These questions have inherent value for understanding normal human physiology, but also directly inform our comprehension of the process by which the system is subverted to drive diseases of the blood, in particular blood cancers and bone marrow failure syndromes. The critical link between normal and abnormal hematopoiesis is perhaps best illustrated by the recent discovery of clonal hematopoiesis in healthy people with no abnormal blood parameters. In such individuals, large clones derived from single cells are present and are dominant relative to their normal counterparts, but their presence does not necessitate abnormal blood cell production. Intriguingly, however, these individuals are also at a significantly greater risk of developing leukemias and of cardiovascular events, underscoring the importance of understanding how blood stem cell clones compete against each other.

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“…Identifying a few regions in the autosomal chromosomes with stable epigenetic states in the hematopoietic lineage could be explored in the future to develop clonality assays for the hematopoietic system. These assays have typically relied on finding significant skewing of the XCI ratio from the 1:1 ratio, which is limited to females and has a low resolution 49 . By focusing on polymorphisms in the autosomal regions with stable epigenetic states, it should be possible to design clonality assays for both sexes that are more sensitive to decreases in clonality than the assays based on XCI.…”

Section: Applications Of Stable Imprints In the Autosomal Regionsmentioning

confidence: 99%

Single-cell reconstitution reveals persistence of clonal heterogeneity in the murine hematopoietic system

Kubasova

Gupta

Vinogradova

et al. 2021

Preprint

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The persistence of patterns of monoallelic expression is a controversial matter. We report a genome-wide in vivo transcriptomics approach based on allelic expression imbalance to evaluate whether the transcriptional allelic patterns of single murine hematopoietic stem cells (HSC) are still present in the respective differentiated clonal B-cell populations. For 14 genes, we show conclusive evidence for a remarkable persistence in HSC-derived B clonal cells of allele-specific autosomal transcriptional states already present in HSCs. In a striking contrast to the frequency of genes with clonal allelic expression differences in clones expanded without differentiation (up to 10%), we find that clones that have undergone multiple differentiation steps in vivo are more similar to each other. These data suggest that most of the random allele-specific stable transcriptional states on autosomal chromosomes are established de novo during cell lineage differentiation. Given that allele-specific transcriptional states are more stable in cells not undergoing extensive differentiation than in the clones we assessed after full lineage differentiation in vivo, we introduce the "Punctuated Disequilibria" model: random allelic expression biases are stable if the cells are not undergoing differentiation, but may change during differentiation between developmental stages and reach a new stable equilibrium that will only be challenged if the cell engages in further differentiation. Thus, the transcriptional allelic states may not be a stable feature of the differentiating clone, but phenotypic diversity between clones of a population at any given stage of the cell lineage is still ensured.

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60 Years of clonal hematopoiesis research: From X-chromosome inactivation studies to the identification of driver mutations

Cited by 26 publications

References 99 publications

Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

Tracking hematopoietic stem cells and their progeny using whole-genome sequencing

Single-cell reconstitution reveals persistence of clonal heterogeneity in the murine hematopoietic system

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