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Lifelong patterns of clonal haematopoiesis revealed

Presented by
Dr Margarete Fabre, University of Cambridge, UK
ASH 2021
A study into the natural history of clonal haematopoiesis revealed that different gene mutations drive different patterns of lifelong clonal behaviour, with DNMT3A, TET2, and spliced mutant clones being the most common drivers. Moreover, the share of oligoclonal clones increases with age. The current characterisation of lifelong natural clonal haematopoiesis offers insights into the interaction between somatic mutations, ageing, and clonal selection [1].

“In normal haematopoiesis, stem cells are homogenous, whereas in clonal haematopoiesis stem cells are genetically diverse due to acquired somatic mutations,” Dr Margarete Fabre (University of Cambridge, UK) explained. “We conducted a study to unravel the transition from normal to clonal haematopoiesis and map the dynamics of clonal haematopoiesis.”

Dr Fabre and colleagues assessed 13 years of blood samples, collected from an elderly population (n=385; mean age at baseline 69.3 years). Deep targeted sequencing was used to detect mutant clones. The results displayed that the mean clone size and number of mutations increased with age, with constant growth rates in >90% of the detected clones. DNMT3A, TET2, and spliced mutant clones were the most common drivers of these mutations. Non-genetic factors accounted for approximately 5% of the clonal growth, proportionally impacting slow driver genes more substantially. Furthermore, mutations associated with faster clonal growth were also associated with an increased risk of acute myeloid leukaemia, independent of clone size.

Next, retrograde extrapolation was performed to assess clonal expansion longitudinally. The results showed that some genetic mutations drive fast clonal expansions early in life and then slow down, such as DNMT3A mutations, whereas other drivers initiate expansion at an older age at a fast growth rate, such as splicing mutations. Still other mutations occur at all ages and demonstrate relatively stable growth, such as TET2-mutant clones (see Figure).

Figure: Different patterns of lifelong clonal behaviour [1]

Whole-genome sequencing of 1,731 single cell-derived colonies confirmed the inferences that were made from the longitudinal data. However, reconstruction of haematopoietic phylogenies showed that many clones lacked recognisable drivers and that these driverless expansions displayed similar growth rates.

In conclusion, the current findings improve the understanding of lifelong clonal behaviour by showing that clonal haematopoiesis is driven by different gene mutations that demonstrate separate patterns of longitudinal clonal behaviour.

  1. Fabre M, et al. The Longitudinal Dynamics and Natural History of Clonal Hematopoiesis. LBA-2, ASH 2021 Annual Meeting, 11–14 December.


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