MPN Driver Mutations May Occur In Utero

A lingering question regarding myeloproliferative neoplasms (MPN)—including polycythemia vera, essential thrombocythemia, and myelofibrosis—is how rapidly they develop. Many patients with MPNs present with normal blood counts just months before diagnosis, supporting a rapid-development model. However, driver mutations are present in the blood of healthy individuals with age-related clonal hematopoiesis, and these may slowly or never evolve into cancer.

“As physicians, some of the commonest questions we get asked by our patients with blood cancers are, ‘How long have I had it for’ and ‘How fast did it grow’” said Jyoti Nangalia, MD, PhD, of the Wellcome Sanger Institute in Hinxton, UK, in a presentation at the 2020 American Society of Hematology Annual Meeting, held virtually December 5–8.Nangalia and her team set out to answer this question using genomic studies—generating highly provocative findings.

The group performed genomic analyses on bone marrow or peripheral blood samples collected from 10 patients diagnosed with MPNs between the ages of 20 and 76. These samples were used to grow single cell–derived hematopoietic colonies, which were subjected to whole-genome sequencing, enabling construction of phylogenetic trees for each patient's clones.

Results from three of the patients, all of whom harbored the most common driver mutation in MPNs, JAK2^V617F, are illustrative. In a patient diagnosed with essential thrombocythemia at age 20, the JAK2^V617F mutation occurred between 6.2 weeks after conception and 1.3 years of age. In a patient with polycythemia vera diagnosed at age 31, the JAK2^V617F mutation became established between 4.2 weeks postconception and 8.6 years of age. Even in the third patient, diagnosed with polycythemia vera at age 65, the mutation was entrenched between 1.8 weeks after conception to 11.4 years of age. The upshot: MPN driver mutations can occur very early in life, perhaps even in utero, and may take decades to progress to full-blown MPNs.

“At any one snapshot in time in our life, the mutations within individual cells represent natural barcodes that can be used to trace back the ancestry of the cells right to the start of life,” Nangalia explained. Using the phylogenetic trees to depict the relative timing of driver-mutation acquisition, the absolute timing of mutation acquisition was determined using patient- and clone-specific mutation rates, revealing the age range during which the mutations likely occurred.

The rate of a clone's growth determined the time between driver mutation and diagnosis. Slower-growing clones could take 50 years to evolve into MPNs, whereas faster-growing clones could become MPNs within 10 years. “For slow-growing JAK2[-mutant] clones, with sensitive assays, we would have been able to detect the clone 40 years before diagnosis, and up to 10 years before diagnosis in faster-growing clones,” Nangalia said.

Ross Levine, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, called the work “interesting and novel,” although he cautioned that the age-of-onset estimates were based on modeling and not experimentally validated.

According to Paresh Vyas, PhD, of the University of Oxford in the UK, the study's modeling techniques are becoming well established, but before the knowledge gained from this work can become useful clinically, researchers need to understand what factors contribute to the trajectory of early JAK2-mutant clones. Knowing what cell-autonomous or non–cell-autonomous factors trigger MPN development from these clones may inform treatment decisions and prevent overtreatment.

Although the study involved a massive sequencing effort, limitations include the small patient sample size, lack of random patient selection, and retrospective nature of the work. Further research to extend and validate the findings in larger, prospective cohorts would enhance the study's impact. –Nicole Haloupek

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