JAK2 V617F allele burden in polycythemia vera: burden of proof

Abstract

Polycythemia vera (PV) is a hematopoietic stem cell neoplasm defined by activating somatic mutations in the JAK2 gene and characterized clinically by overproduction of red blood cells, platelets, and neutrophils; a significant burden of disease-specific symptoms; high rates of vascular events; and evolution to a myelofibrosis phase or acute leukemia. The JAK2V617F variant allele frequency (VAF) is a key determinant of outcomes in PV, including thrombosis and myelofibrotic progression. Here, we critically review the dynamic role of JAK2V617F mutation burden in the pathogenesis and natural history of PV, the suitability of JAK2V617F VAF as a diagnostic and prognostic biomarker, and the utility of JAK2V617F VAF reduction in PV treatment.

Graphical abstract

Figure 1.

Quantitative, qualitative, and clonal burden in PV. (A) JAK2^V617F increases cell quantity by transmitting an excessive growth signal that induces a blood stem cell with the mutation to over produce red blood cells, white blood cells, and platelets. (B) JAK2^V617F excessive signaling in cells turns on ROS and HIF, resulting in activation of pathways within the HSC cell, the bone marrow niche, and beyond. (C) JAK2^V617F can be present in a single cell as a single copy (heterozygote, blue circle) or as a double copy (homozygote, red circle). Measured JAK2^V617F VAF in PV may range from 1% to 100%, depending on relative quantities of the various JAK2^V617F genotypes. HIF, hypoxia-inducible factor; ROS, reactive oxygen species.

Figure 2.

PV clinical and research goals. The 2005 JAK2^V617F discovery opened new windows for the understanding and treatment of PV. Hydroxyurea and phlebotomy have been used in the past and at present to manage cytoses. In 2014, the first targeted therapy, ruxolitinib, was approved for PV. More recently the focus has shifted to understanding disease latency and targeting clonal expansion, and ropeginterferon was approved in 2021.