Mechanisms of thrombogenesis in polycythemia vera.
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ABSTRACT:
SUBMITTER: Kroll MH
PROVIDER: S-EPMC4466074 | biostudies-literature | 2015 Jul
REPOSITORIES: biostudies-literature
Publications
Mechanisms of thrombogenesis in polycythemia vera.
Kroll Michael H MH Michaelis Laura C LC Verstovsek Srdan S
Blood reviews 20141213 4
Thrombotic and cardiovascular events are among the leading causes of death for patients with polycythemia vera (PV), and thrombosis history is a key criterion for patient risk stratification and treatment strategy. Little is known, however, about mechanisms of thrombogenesis in patients with PV. This report provides an overview of thrombogenesis pathophysiology in patients with PV and elucidates the roles of conventional and nonconventional thrombotic risk factors. In addition to several convent ...[more]
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Project description:Polycythemia vera (PV) is an acquired blood disorder, with variable increase of clonal myeloid cells (erythrocytes, granulocytes and platelets) and mostly normal polyclonal T lymphocytes. Most patients have a somatic V617F gain-of-function mutation in JAK2 associated with acquired uniparental disomy (UPD) on chromosome 9p. Yet, the JAK2 V617F mutation is not a PV-initiating event and the family clustering of PV suggests a contribution of inherited genetic events. Using whole-genome SNP arrays, we assayed 34 T-cells and 66 granulocytes (including 32 pairs from the same patients), and identified multiple SNPs around JAK2 that are associated with PV susceptibility (rs11999802, P=1.8E-8, OR=4.4). We also developed a quantitative measure of the fraction of somatic single nucleotide variants (SNVs) based on allele-specific PCR, and a quantitative measure of somatic UPD based on "fractional copy-neutral loss-of-heterozygosity (LOH)" on SNP arrays. Somatic genomic changes in granulocytes revealed strong genetic heterogeneity, including 9p UPD and chromosomal gain. The magnitude of somatic 9p UPD was strongly associated with V617F dosage (r2=0.74, P=4.8E-12), suggesting that UPD preferentially increases the V617F subclone. In granulocytes with heterozygous rs11999802 genotypes, UPD increased the relative fraction of germline risk alleles (P=0.03). Thus, germline risk variants at JAK2 predispose to somatic point mutations within JAK2, whose allelic dosage can be further increased by a serial subclonal expansion of allele-specific UPD or copy number alteration, contributing to PV pathogenesis. We argue that PV represents a unique disease model to study the interplay between germline risk variants and convergent mechanisms of somatic mutations.
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Project description:Polycythemia vera (PV) is a clonal disorder resulting from neoplastic transformation of hematopoietic stem cells, while secondary polycythemia (SP) is a disease characterized by increased absolute red blood cell mass caused by stimulation of red blood cell production. Although the physiopathology of SP and PV is distinct, patients with these diseases share similar symptoms. The early differential diagnosis may improve the quality of life and decrease the disease burden in PV patients, as well as enable curative treatment for SP patients. PV is considered an oncoinflammatory disease because PV patients exhibit augmented levels of several pro-inflammatory cytokines. In this sense, we examined whether analysis of the cytokine production profile of SP and PV patients would help to distinguish them, despite their clinical similarities. Here we reported that SP patients exhibited decreased plasma levels of, IL-17A, IFN-γ, IL-12p70 and TNF-α when compared with PV patients, suggesting that analysis of the cytokine production profile may be an useful diagnostic biomarker to distinguish PV from SP patients.
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