Understanding who develops which MPN and why
Jyoti Nangalia, MBBS, PhD
Wellcome Sanger Institute
It is known that JAK2 mutations are found in “healthy” people around the world, particularly in older individuals. Most of them don’t acquire characteristics of myeloproliferative neoplasms (MPNs). The question is why do some people with the mutation develop an MPN while others don’t.
Researchers from the Wellcome Sanger Institute, the University of Cambridge, and other collaborators combined three key data sets to answer this and other related questions in a recently published study in the monthly journal Nature Genetics, titled: Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms.
There was previously little understanding of why a minority of people with mutated JAK2 genes go on to develop MPNs – the group of rare chronic blood cancers that includes essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Also unclear were the factors that influence blood heterogeneity in MPNs, including the differences in gene mutations, MPN driver genes, such as JAK2.
“This study aims to understand how the DNA that people are born with can affect the type of MPN they might develop, or indeed, the type of MPN they are less likely to develop,” explains Jyoti Nangalia, MBBS, PhD, of Wellcome Sanger Institute and the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge. She is co-senior author of the study and also a member of MPN Research Foundation’s Scientific Advisory Board.
“I hope that, in the future, this information will help us predict which individuals are most likely to develop MPN if they are found to have a JAK2 mutation, and the type of MPN they may be predisposed to,” Dr. Nangalia adds.
Physicians use blood tests to help diagnose and manage MPNs, including the number of circulating blood cells (red cells, white cells, and platelets), and the presence and prevalence of any identified genetic mutations.
In the published study, the authors describe their work specifically:
“By analyzing two large MPN disease cohorts and the UK Biobank (UKBB), we provide new insights into the interaction between germline polygenic variation involved in basic hematopoiesis and clonal selection on somatic driver mutations in blood and describe how this interaction can influence the phenotype of subsequent blood cancer.”
In other words, blood cells with the MPN driver mutations also need the right genetic environments to ultimately lead to an MPN diagnosis.
The authors conclude: “Our results highlight an independent and causal new component of the overall susceptibility to clonal disease and provide a new framework for considering an individual’s genetic background in the context of their clinical presentation.”
Earlier work by Dr. Nangalia et al was funded by MPN Research Foundation through the 2019 MPN Challenge™, Origins of MPN: Understanding the timing of acquisition of driver mutations and dynamics of clonal expansion, and received global attention for its new evidence that JAK2 MPN mutations can be identified from birth and earlier.
The new study published in January 2024 is related. “Previously MPNRF has funded our work exploring when in life the mutations that cause MPN are acquired. This study now sheds light on why such mutations result in overgrowth of bone marrow cells in some individuals more than others,” says Dr. Nangalia.
In Nature Genetics, the researchers report combining information on the known somatic driver mutations in MPN, inherited genetic variants, and genetic risk scores from individuals with MPN.
- The goal was to obtain a more complete picture of how these variants combine to cause blood disorders.
- They found that the inherited variants that cause natural blood cell variation in the population also impact whether a JAK2 somatic mutation will go on to cause MPN.
- They also found that individuals with an inherited risk of having a higher blood cell count could display MPN features in the absence of cancer-driving mutations, thus mimicking disease.
https://pubmed.ncbi.nlm.nih.gov/38233595/
Guo J, Walter K, Quiros PM, Gu M, Baxter EJ, Danesh J, Di Angelantonio E, Roberts D, Guglielmelli P, Harrison CN, Godfrey AL, Green AR, Vassiliou GS, Vuckovic D, Nangalia J, Soranzo N. Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms. Nat Genet. 2024 Feb;56(2):273-280. doi: 10.1038/s41588-023-01638-x. Epub 2024 Jan 17. PMID: 38233595; PMCID: PMC10864174.