Environmental influences on clonal hematopoiesis

King, Katherine Y.; Huang, Yun; Nakada, Daisuke; Goodell, Margaret A.

doi:10.1016/j.exphem.2019.12.005

Cited by 50 publications

(32 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Restriction of the clonal hematopoietic diversity, a phenomenon known as clonal hematopoiesis of indeterminate potential (CHIP), is a frequent feature of aging that may precede the emergence of hematologic malignancies. 44,45 CHIP is associated with an increase in the likelihood of having type II diabetes, but the causal link between these conditions has not been established. Thus, it is possible that CHIP-associated inflammation promotes diabetes and/or that diabetic conditions alter hematopoietic clonal diversity.…”

Section: Discussionmentioning

confidence: 99%

FOXO activity adaptation safeguards the hematopoietic stem cell compartment in hyperglycemia

et al. 2020

View full text Add to dashboard Cite

Hematopoietic stem cell (HSC) activity is tightly controlled to ensure the integrity of the hematopoietic system during the organism’s lifetime. How the HSC compartment maintains its long-term fitness in conditions of chronic stresses associated with systemic metabolic disorders is poorly understood. In this study, we show that obesity functionally affects the long-term function of the most immature engrafting HSC subpopulation. We link this altered regenerative activity to the oxidative stress and the aberrant constitutive activation of the AKT signaling pathway that characterized the obese environment. In contrast, we found minor disruptions of the HSC function in obese mice at steady state, suggesting that active mechanisms could protect the HSC compartment from its disturbed environment. Consistent with this idea, we found that FOXO proteins in HSCs isolated from obese mice become insensitive to their normal upstream regulators such as AKT, even during intense oxidative stress. We established that hyperglycemia, a key condition associated with obesity, is directly responsible for the alteration of the AKT-FOXO axis in HSCs and their abnormal oxidative stress response. As a consequence, we observed that HSCs isolated from a hyperglycemic environment display enhanced resistance to oxidative stress and DNA damage. Altogether, these results indicate that chronic metabolic stresses associated with obesity and/or hyperglycemia affect the wiring of the HSCs and modify their oxidative stress response. These data suggest that the uncoupling of FOXO from its environmental regulators could be a key adaptive strategy that promotes the survival of the HSC compartment in obesity.

show abstract

Section: Discussionmentioning

confidence: 99%

FOXO activity adaptation safeguards the hematopoietic stem cell compartment in hyperglycemia

et al. 2020

View full text Add to dashboard Cite

show abstract

“…An increase in RDW is often observed in individuals exhibiting the clonal expansion of haematopoietic stem and progenitor cells (HSPCs), that is, clonal haematopoiesis (CH), which is prevalent in those around the age of 70 years or older 13 . Clonal chromosome aberrations frequently observed in A‐bomb survivors were in some cases derived from the clonal expansion of HSPCs, 14 implicating the emergence of radiation‐related CH, which could accompany reduced HSPC pool sizes, induced somatic mutations, and stimulated inflammatory signalling 15 . An evolving hypothesis is that prior radiation exposure can cause an elevation of RDW through the expansion of particular HSPC clones with somatic mutations.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal changes in red blood cell distribution width decades after radiation exposure in atomic‐bomb survivors

et al. 2020

View full text Add to dashboard Cite

Red blood cell distribution width (RDW), which generally increases with age, is a risk marker for morbidity and mortality in various diseases. We investigated the association between elevated RDW and prior radiation exposure by examining longitudinal RDW changes in 4204 atomic-bomb survivors over 15 years. A positive association was found between RDW and radiation dose, wherein RDW increased by 0Á18%/Gy. This radiation-associated effect increased as the participants aged. Elevated RDW was also associated with higher all-cause mortality. The biological mechanisms underlying these observed associations merit further investigation.

show abstract

“…57 All of these challenges that reduce HSC numbers have been associated with the occurrence of clonal hematopoiesis -the over-representation of a single clone in the blood or bone marrow. [58][59][60] But the respective role of natural selection and neutral evolution in these clonal expansions has yet to be fully elucidated. The fact that synonymous (non-functional) mutations are rarely observed at high allele frequency in the blood of healthy people is good evidence in favor of natural selection in clonal hematopoiesis.…”

Section: Is the Number Of Contributing Hscs Compatible With Genetic Dmentioning

confidence: 99%

To portray clonal evolution in blood cancer, count your stem cells

Lyne

Laplane

Perié

2021

Blood

View full text Add to dashboard Cite

Clonal evolution, the process of expansion and diversification of mutated cells, plays an important role in cancer development, resistance and relapse. While clonal evolution is most often conceived of as driven by natural selection, recent studies uncovered that neutral evolution shapes clonal evolution in a significant proportion of solid cancers. In hematological malignancies, the interplay between neutral evolution and natural selection is also disputed. Because natural selection selects cells with a higher fitness-providing a growth advantage to some cells relative to others-the architecture of clonal evolution serves as indirect evidence to distinguish natural selection from neutral evolution and has been associated with different prognoses for the patient. Linear architecture, when the new mutant clone grows within the previous one, is distinctive of hematological malignancies and typically interpreted as driven by natural selection. Here we wish to discuss the role of natural selection and neutral evolution in the production of linear clonal architectures in hematological malignancies. While it is tempting to attribute linear evolution to natural selection, we argue that a lower number of contributing stem cells accompanied by genetic drift can also result in a linear pattern of evolution as illustrated by simulations of clonal evolution in hematopoietic stem cells. The number of stem cells contributing to long-term clonal evolution is not known in the pathological context and we advocate that estimating these numbers in the context of cancer and ageing is crucial to parsing out neutral evolution from natural selection, two processes that require different therapeutic strategies.

show abstract

Environmental influences on clonal hematopoiesis

Cited by 50 publications

References 78 publications

FOXO activity adaptation safeguards the hematopoietic stem cell compartment in hyperglycemia

FOXO activity adaptation safeguards the hematopoietic stem cell compartment in hyperglycemia

Longitudinal changes in red blood cell distribution width decades after radiation exposure in atomic‐bomb survivors

To portray clonal evolution in blood cancer, count your stem cells

Contact Info

Product

Resources

About