Highlights from

ASH 2020

62nd Annual Meeting & Exposition of the American Society of Hematology

Virtual 5 - 8 December 2020

Myeloproliferative neoplasm-related mutations are acquired as early as in utero or childhood

In the pathogenesis of myeloproliferative neoplasms (MPN), driver mutations in the JAK2 and DNMT3A genes are acquired as early as in utero and in childhood. In addition, British researchers found variable rates of clonal expansion. Sequential acquisition of driver mutations is separated by decades and is associated with rapid growth. Expansion rates determine latency to diagnosis. Insights in mutation rates and rate of expansion could enable preventative strategies.

Dr Nicholas Williams (Wellcome Sanger Institute, United Kingdom) and colleagues aimed to identify the timing of driver mutations and clonal dynamics in adult patients with an MPN. The investigated cohort consisted of 10 patients with MPN who presented with a variety of phenotypes; age ranged from 20 to 76 years. Of each of these patients, samples from peripheral blood and bone marrow were taken. Whole-genome sequencing was performed on individual single-cell derived haematopoietic colonies.

Sequencing results showed an abundance of driver mutations, almost 450,000, both in genes associated with MPN and cancer, but also copy number changes. Somatic mutations were used to reconstruct phylogenetic trees of haematopoiesis. Driver mutations were assigned on the tracing blood cell lineages back to embryogenesis. The timing of driver mutations on the branches of the tree gave the relative timing and ordering of mutations in that individual patient. Most importantly, the investigators then converted relative timing to absolute timing, because the absolute number of somatic mutations in an individual colony accurately reflects the age of the patient.

In all patients in whom JAK2 V617F was the first or only driver mutation, this mutation was acquired in utero or childhood. This mutation was found to occur as early as within a few weeks after conception. Upper estimates of age of acquisition were between 4.1 months and 11.4 years, although ages of MPN presentation ranged substantially. DNMT3A mutations are the most common in age-related clonal haematopoiesis. These mutations occurred as the first driver event, subsequent to mutated JAK2, and as independent clones representing clonal haematopoiesis in MPN patients. DNMT3A mutations were also first acquired in utero or childhood, ranging from 1.2 weeks after conception to 7.8 years.

Interestingly, across this cohort within individual patients, the same or similar genetic aberrations were observed repeatedly in unrelated clones. Such ‘parallel evolution’ suggests that other factors than the driver mutations are predisposing patients to select for certain driver mutations, such as their germline background or the micro-environment within the bone marrow.

  1. Williams N, et al. Driver Mutation Acquisition in Utero and Childhood Followed By Lifelong Clonal Evolution Underlie Myeloproliferative Neoplasms. 62nd ASH Annual Meeting, December 5-8, 2020. Abstract LBA-1.

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