New insights into genetics of MPN

Myeloproliferative neoplasms (MPN) originate from driver mutation acquisitions very early in life, even before birth, with life-long clonal expansion and evolution. Early detection of mutant JAK2, together with determination of clonal expansion rates, could provide opportunities for early interventions, minimising thrombotic risk and targeting the mutant clone in at-risk individuals [1].

The genetic basis of the 3 types of MPN –polycythaemia vera, essential thrombocythaemia, and myelofibrosis– is well characterised [1]. Dr Jyoti Nangalia (University of Cambridge, United Kingdom) told during the late-breaking session: “Over 90% of patients harbour a mutation in JAK2, CALR, or MPL genes; 60% harbour mutations in additional cancer-associated genes, particularly TET2, a chromosomal aberration of 9 (Chr9), ASXL-1, and DNMT3A” [2].

The investigated cohort consisted of 10 patients with MPN who presented with a variety of phenotypes. Age ranged from 20 to 76 years. Samples from peripheral blood and bone marrow were taken of each patient. Whole-genome sequencing was performed of individual single-cell derived haematopoietic colonies. “The reason we did this, is that right from the start of life, all cells are acquiring mutations,” Dr Nangalia explained. “Mutations in individual cells act as natural barcodes. They are passed down from generation to generation. So, mutations can trace family relationships back to the start of life. We did this in MPN.”

The researchers found an abundance of driver mutations, almost 450,000, both in genes associated with MPN and cancer, but also copy number changes. These somatic mutations were used to reconstruct the phylogenetic trees of haematopoiesis. They then assigned driver mutations on the tracing blood cell lineages back to embryogenesis. “Most importantly, we 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 [1].”

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. The mean latency between JAK2-V617F acquisition and clinical presentation was 34 years (range 20-54 years). Subsequent driver mutation acquisition, including for JAK2-V617F, was separated by decades. Disease latency following acquisition of JAK2-V617F as a second driver event was still 12-27 years.

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.

1. Williams N, et al. Driver Mutation Acquisition in Utero and Childhood Followed By Lifelong Clonal Evolution Underlie Myeloproliferative Neoplasms. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract LBA-1.
2. Nangalia J, et al. N Engl J Med. 2013;369:2391-405.

Posted on 18 February 202118 February 2021