Cancer

Bad blood promotes tumour progression

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Mutations that drive the abnormal expansion of progenitor subpopulations of blood cells are known to cause leukaemia. A genetic analysis reveals that these clonal blood stem-cell mutations are also common in people who have solid tumours.

The acquisition of mutations in blood-forming (haematopoietic) stem cells can lead to a process called clonal haematopoiesis, in which subpopulations of mutant blood cells arise. This phenomenon can be a treacherous contributor to the progression of leukaemia and death. Writing in Cell Stem Cell, Coombs et al.1 provide evidence that clonal haematopoiesis is also common in people who have solid tumours. In these people, the phenomenon is associated with increased age, tobacco use and radiation therapy, is correlated with an increased risk of leukaemia, and is linked to reduced overall survival.

The idea of clonal haematopoiesis dates back to 1960, when a chromosomal abnormality in blood cells was first associated with cancer2 — specifically, with chronic myeloid leukaemia (CML). Subsequently, evidence emerged3 that the bone-marrow disorder polycythaemia vera (which, like CML, involves enhanced proliferation of blood cells) derives from defective haematopoietic stem cells (HSCs). Studies in mice4,5,6 pinned down the functional impact of specific mutations involved in these diseases, and analysis7,8 of patient-derived bone marrow confirmed that the mutations identified in mice also arise in human HSCs. Cumulatively, these studies proved that both pre-leukaemic disorders (such as myeloproliferative neoplasms and myelodysplastic syndrome) and leukaemia itself can arise from clonal haematopoiesis.

More recently, an analysis9 of the protein-coding DNA of 17,182 people demonstrated that clonal haematopoiesis occurs with ageing. The study revealed that variants in three genes (DNMT3A, TET2 and ASXL1) occurred in the blood cells of more than 9.5% of individuals older than 70. These variants conferred a higher risk of leukaemia, coronary heart disease, stroke and death. But this work, although seminal, did not address a possible relationship between clonal haematopoiesis and solid tumours.

To investigate the possibility of such a link, Coombs et al. sequenced matched blood and tumour samples from 8,810 individuals with solid tumours. In particular, they analysed the protein-coding sequences of either 341 or 410 cancer-associated genes, with more genes being analysed in patients enrolled later in the study. This revealed clonal haematopoiesis in 25.1% of people with solid tumours. About 4.5% of them had mutations previously shown to promote leukaemia, including those in the genes TP53 and PPM1D. These mutations were associated with exposure to chemotherapy, an increased rate of leukaemia and lower survival rates.

The authors followed the progress of 5,394 of the patients for between 12 and 21 months. Notably, 19 individuals developed some form of blood cancer after the matched blood and tumour samples were taken. The likelihood of this occurring was statistically higher for patients who had clonal haematopoiesis, thereby underscoring the impact of this phenomenon on both cancer initiation and progression.

Strikingly, the cause of death in 98% of the patients who died during the study was solid-tumour progression. Together, then, Coombs and colleagues' findings demonstrate that the risk of a cancer progressing is higher if an individual carries a mutation that causes clonal haematopoiesis. Extrinsic influences such as chemotherapy and radiation therapy, although aimed at keeping solid tumours at bay, might also cause mutations that enhance the fitness of clonal HSCs. In doing so, they could actually contribute to solid-tumour progression (Fig. 1), by providing microenvironmental cues that act to promote the fitness of solid-tumour stem cells. This will need to be investigated in further studies.

Figure 1: From haematopoietic stem cells (HSCs) to solid tumours.
figure1

Smoking, ageing and toxic treatments such as chemotherapy or radiation therapy can all cause mutations in blood-forming HSCs. If these mutations confer a fitness advantage, they can trigger clonal haematopoiesis — a phenomenon in which mutant subpopulations of blood cells expand to form a population of pre-leukaemic cells. This, in turn, can lead to leukaemia. Coombs et al.1 have demonstrated that clonal haematopoiesis is associated with the progression of solid tumours, presumably owing to interactions between the cells of these tumours and pre-leukaemic cells. (Figure based on a graphic from ref. 1.)

It is possible that the mutations observed by Coombs et al. in PPM1D and some other genes are germline (inherited) mutations, and so are present in all cells of the body, rather than arising specifically in HSCs. However, a major contribution of germline mutations to clonal haematopoiesis, which usually emerges with advanced age, seems unlikely. Moreover, the association between clonal haematopoiesis during ageing and the development of leukaemia suggests that these mutations are drivers of cancer, rather than passengers, again arguing against a germline origin. Nonetheless, the functional contribution of inherited mutations to clonal haematopoiesis and tumour progression has not been fully explored and should be addressed in future.

Clonal haematopoiesis has been thought of as caused mainly by DNA mutations acquired during ageing9,10. But equally important might be ageing-associated disruption of RNA processing. Such disruption induces a loss of normal human HSC dormancy, survival and self-renewal, and thus reduces overall HSC fitness11. In addition to these cell-intrinsic injuries to DNA and RNA, mutations in both molecules can be induced during ageing by extrinsic inflammatory signalling molecules and metabolic dysfunction12,13,14,15,16. These factors, too, might enhance clonal haematopoiesis and the development of both blood-related and solid tumours.

As a body of work, research into clonal haematopoiesis is shedding light on the fuel that feeds cancer. Perhaps by understanding that we cannot always eradicate tumours without correcting the 'bad blood' within them, we will be able to devise more-effective cancer eradication strategies.Footnote 1

Notes

  1. 1.

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Jamieson, C. Bad blood promotes tumour progression. Nature 549, 465–466 (2017). https://doi.org/10.1038/549465a

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