Polycythemia Vera (PV)

Image source: Wellcome Library, London


Polycythemia vera (PV) is an acquired clonal hematopoietic stem cell disease characterized by an elevated red cell mass caused by excessive myelopoiesis with propensity to transformation to myelofibrosis and acute leukemia. JAK2V617F mutation and acquired uniparental disomy on chromosome 9p (9p aUPD) are the most frequent somatic alterations. JAK2 is mutated in over 90% of PV patients; however, in spite of its prevalence it is regarded as necessary by not sufficient to cause the disease. Yet, the full mutation landscape, the order of significant somatic events, whether and how these alterations contribute to disease initiation, clonal evolution or myelofibrotic transformation, the relationship between JAK2V617F and 9p aUPD, the frequency and stability of existing PV genotypes has to be systematically investigated in a larger PV cohort.


With the collaboration of the Hematology Division, Department of Internal Medicine, and The University of Utah School of Medicine, we have collected granulocytes, their matched T-cell and skin biopsies samples from more than 30 PV patients.

We applied whole-exome sequencing, targeted deep sequencing and high-resolution snp arrays to investigate the somatic mutations, germline variants and DNA copy-number alterations.

We defined 4 PV subgroups based on the quantitative relationship between JAK2V617F and 9p aUPD and identified a novel PV subtype, aUPD with heterozygous JAK2V617F in 10% of PV patients.

In addition to JAK2 V617F and 9pUPD, we identified frequent recurrent somatic mutation in ASXL1, TET2, DNMT3A, SF3B1 and NF1. Forty two percent of patients had a somatic mutation in at least one epigenetic modifier gene. In 4 patients, variant allele abundance suggested mutation of JAK2V617F was preceded by other somatic mutations including ASXL1, DNMT3A and SF3B1. Strikingly, in 7 patients, apparent germline variants were detected at COSMIC codons in one or more PV-related genes in which we had also discovered somatic mutations across the cohort, suggesting that some pre-JAK2V617F mutations contribute to substantial T-lymphocyte progeny.

This study contributes to novel understanding of the complexity of PV pathogenesis.