With time, genes in all cells of the body incorporate mutations. When blood cells pick up specific “driver” mutations, they divide and multiply faster than their peers, to form populations with identical mutations (clones). This process of expansion (clonal hematopoiesis) of mutant blood cells, can lead to certain blood cancers (myeloid neoplasias, leukemias). The process and timing of clonal hematopoiesis, factors influencing it, and its interactions with aging and cancer have been unclear, until now.

“Clonal hematopoiesis becomes common with age to affect most people older than 70 years. These clones are the origins of several types of leukemia and related cancers. We wanted to understand how these clones expand over time and if their dynamic behavior related to the likelihood of progressing to leukemia,” said George Vassiliou, PhD, formerly from the Wellcome Sanger Institute, and currently a professor of hematology at the Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, U.K.

In a new study “The longitudinal dynamics and natural history of clonal haematopoiesis” published on June 1, 2022, in the journal Nature, Vassiliou and his colleagues, track and model 697 clones of blood cells from 385 people over 13 years. The study uncovers how specific mutations in blood cell clones predominate at different periods of life. This is the first study to explore the effects of mutations on lifelong cell growth changes. Participants included in this study were 55 years or older who were recruited as part of the SardiNIA longitudinal study.

From left to right: Lead authors Margarete Fabre and Jose Guillherme de Almeida, and senior authors Moritz Gerstung and George Vassiliou.

“We found that in old age most clones expand at a steady exponential rate. The rate depended on the identity of the gene carrying the driver mutation. For many clones, the rates of expansion were too slow to explain their size. This, combined with phylodynamic analyses, revealed that some clones expanded primarily earlier in life and then slowed down (e.g., those with DNMT3A mutations),” said Vassiliou. “By contrast other clones did not expand in young age but did so at old age at a rate that exceeded all other clones (e.g., clones with mutations in the splicing genes SRSF2 and U2AF1). Another set of clones were not significantly affected by age (e.g., clones with mutations in the TET2 gene). Strikingly, these behaviors appear to anticipate the age-distribution of different types of blood cancers.”

Clonal trajectories
Individual clone trajectories [George Vassiliou]
“For the first time we have been able to use genomic analysis to understand the past, present and future of mutant clones in our blood. These data show that the dynamics of blood clones are surprisingly predictable over a period of years, but also highlight that they change over a lifetime in ways we don’t understand yet,” said Moritz Gerstung, PhD, a co-senior author of the study and professor at the European Bioinformatics Institute at the European Molecular Biology Laboratory (EMBL) and the German Cancer Research Centre (DKFZ).

Margarete Fabre, first author of the paper and a PhD student at the Wellcome Sanger Institute and the University of Cambridge, said, “Our findings reveal how acquired genetic changes hijack blood formation during our lifetimes, with normal blood stem cells competing against cells with pre-leukemia mutations. Understanding why some mutations prevail in youth and others in old age could help us find ways to maintain the health and diversity of our blood cells.”

Through DNA sequencing of the blood samples collected, the researchers noted that 92.4% clones expanded at a stable exponential rate throughout the duration of the study, with different mutations driving different rates of growth. For example, whereas mutations in genes like DNMT3A (that encodes an enzyme that catalyzes DNA methylation) and TP53 (a tumor suppressor gene) resulted in a 5% growth rate in blood cells, mutations in splicing genes like SRSF2 resulted in a growth rate of over 50%, annually.

In blood cells bearing the same mutation, the authors found growth rates varied by around 5% per year, with greater effects on cells bearing mutations that drove slow growth rates.

The investigators then combined their time-series data with phylogenetic analysis of 1,731 whole genome-sequenced hematopoietic colonies from seven older individuals to generate mathematical models that uncovered patterns of clonal growth rate dynamics over the lifetime. They showed blood cell clones with mutations in the DNMT3A gene expanded more in youth and less in old age while clones with splicing gene mutations only triggered clonal expansion later in old age life, and clones with mutations in TET2, a gene that encodes an enzyme that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine, emerge throughout life.

“Previous studies inferred the rate of expansion of clones by the size the clones reached when they were identified. This assumed a steady expansion through life,” said Vassiliou said. “Instead, we analyzed multiple blood samples obtained serially over a median of 13 years and used single-cell-based phylodynamic analyses to capture the historical behavior of these clones.”

In addition, the authors showed age-dependent clonal growth dynamics mirror the frequencies of different blood cancers, indicating mutations that drive faster growth of clones are more likely to develop into blood cancers.

“Our work reveals an astonishing interaction between advancing age and mutations in the DNA of our blood cells that is played out as the expansion of cells with different mutations at different ages,” said Vassiliou. “Remarkably, these changes lead to the emergence of different types of blood cancers at different ages, and with different risks of progression. With this new understanding, researchers can begin to develop approaches and treatments to stop the development of blood cancer in its tracks.”

“This groundbreaking study tracked the growth of mutant clones in blood in the largest longitudinal dataset of clonal hematopoiesis to date. They were able to identify that different driver genes had different growth rates. Within individuals, nearly 90% clones grew at a constant rate over the study period, which suggests that an aging microenvironment does not play a major role in accelerating clonal expansion,” said Siddhartha Jaiswal, PhD, assistant professor of pathology at Stanford University whose lab focuses on the biology of the aging hematopoietic system. Jaiswal was not involved in the current study and is the co-author of a commentary on the study published in Nature Cardiovascular Research. “The most surprising finding in the study was the observation that clones with DNMT3A mutations, the most common lesion in clonal hematopoiesis, grew faster earlier in life but slowed down with aging, which is the opposite of what many would have predicted.”

Jaiswal added, “The major limitation of the research is that it was likely underpowered for identifying other factors associated with clone growth, such as inherited genetic variants or inflammatory biomarkers. Much larger studies would be needed to robustly assess for these associations.”

Matteo Della Porta, PhD, professor of hematology and head of the leukemia unit at Humanitas University, Italy, noted, “This study provides new insights into the lifelong dynamics of clonal hematopoiesis and the processes linking somatic mutation, clonal expansion and malignant progression. These findings are expected to have relevant practical implications in clinical monitoring of subjects with clonal hematopoiesis and in refining the capability to identify individuals at high risk of developing myeloid malignancies.”

Della Porta, who was not involved in the current study, added, “The time and place of individual mutations and their clonal emergence during the course of the disease are central issues for a better comprehension of myeloid neoplasms pathogenesis and phenotype, for the development of cancer preventive strategies and for the design of potentially new therapeutic strategies in high risk individuals to eradicate clones harboring the genetic aberrations that accumulate in hematopoietic cells.”

In their future experiments, Vassiliou and his team intend to explore the reasons underlying the expansion of certain clones during specific periods in life with the goal of therapeutically modulating clonal expansion to avert leukemia.

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