MPN mutations – further research showing they are often acquired in utero or early childhood

This year has seen two significant bodies of work published about the timing of the acquisition of blood cancer mutations in patients with myeloproliferative neoplasms (MPNs).
These findings lend further support to earlier research that, in many cases, these mutations occurred in utero or early childhood. They also have broader implications for cancer patients.

1. The first paper, ‘Life histories of myeloproliferative neoplasms inferred from phylogenies’ was published in Nature 19 January 2022, by researchers from the Wellcome Sanger Institute and the University of Cambridge.
Researchers found that mutations that cause MPNs have been traced to acquisition in childhood or even in utero, suggesting that cancer causing events can arise in early life and grow over decades before leading to symptoms.  This research further suggests that these mutations will cause blood cells to multiply at different rates in different people, and those in whom these mutations cause faster growth have cancer symptoms appearing earlier. If these mutations proliferate slowly, it is possible that the cancer symptoms would never appear, or be noticed after death by other causes.

Leading MPN researcher and haematologist Jyoti Nangalia, a senior author on the study and who also earlier discovered the CalR mutation in MPNs, advised that ‘This is not something we were expecting. Blood cancer impacts thousands of lives every day and research such as ours into the timing and pace of how different cancers develop is crucial if we are going to find new ways to prevent these conditions. The success of our approach for tracking the origin and growth of this blood cancer could be applied to many other cancers and diseases.’

Further work is now needed to understand how this information could help predict cancer risk in people with these mutations. In addition to early detection, research is also needed into whether current treatments or new therapies could be used to slow or prevent the development of cancer once a person is identified as ‘at risk’.

This is ground-breaking work for MPN patients.  A summary of the findings is available HERE.

2. The second body of work is titled ‘In utero origin of myelofibrosis presenting in adult monozygotic twins

This research from a team of Oxford researchers which included lead MPN researcher and haematologist Adam Mead, identified three patients presenting in their 30s with an MPN who had acquired their initiating somatic driver mutation by a single cell in utero.
The paper describes a case of monozygotic twins presenting with CALR mutation-positive primary myelofibrosis when aged 37 and 38 years. Researchers were able to determine that the CALR mutation was a somatic acquisition, not germline. Their whole-genome sequencing lineage tracing revealed a common clonal origin of the CALR-mutant MPN clone, which occurred in utero followed by twin-to-twin transplacental transmission and subsequent similar disease latency. Hematopoietic stem cells (HSCs) were identified as the likely MPN-propagating cell.

A third patient in the study presented with polycythemia at 34 years. A neonatal blood spot analysis confirmed in utero origin of the JAK2V617F mutation.
These findings provide a unique window into the prolonged evolutionary dynamics of MPNs and fitness advantage exerted by MPN-associated driver mutations in HSCs.

A link to the full paper is not paywalled and is available in Nature Medicine ‘In utero origin of myelofibrosis presenting in adult monozygotic twins’.


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