JAK2 V617F allele burden in polycythemia vera: burden of proof

Abstract

Polycythemia vera (PV) is a hematopoietic stem cell (HSC) neoplasm defined by activating somatic mutations in the JAK2 gene and characterized clinically by overproduction of red blood cells, platelets, and neutrophils; 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. Herein we critically review the dynamic role of JAK2V617F mutation burden in the pathogenesis and natural history of PV, suitability of JAK2V617F VAF as a diagnostic and prognostic biomarker, and utility of JAK2V617F VAF reduction in PV treatment.

Clonal dynamics and copy number variants by single‐cell analysis in leukemic evolution of myeloproliferative neoplasms

“…Studies pointed to clonal evolution as being relevant for changes in clinical phenotype in MPN. 34 Emergence of JAK2V617F homozygous clones in PV is associated with higher rate of transformation to postPVmyelofibrosis and thrombotic events [35][36][37][38] and to myelofibrotic transformation in ET. 36,39 However, before being able to prospectively value the changes of tumor clone asset for clinical purposes, aimed at identifying patients in need of closer monitoring and, prospectively, earlier intervention, a deeper knowledge of clonal dynamics along the MPN natural history, also envisioning patients with decade-long uncomplicated disease, is needed.…”

“…Thus, one might anticipate that serial analysis of clonal dynamics by SCS might allow to precociously identify the emergence and expansion of clone(s) harboring mutation(s) with leukemic potential. Studies pointed to clonal evolution as being relevant for changes in clinical phenotype in MPN 34 . Emergence of JAK2 V617F homozygous clones in PV is associated with higher rate of transformation to postPV‐myelofibrosis and thrombotic events 35–38 and to myelofibrotic transformation in ET 36,39 .…”

Genetic mutations in pyoderma gangrenosum, hidradenitis suppurativa, and associated autoinflammatory syndromes: Insights into pathogenic mechanisms and shared pathways

“…33 Enhanced JAK2 V617F signal transduction leads to abnormal overproduction of neutrophils, red blood cells, and platelets in individuals with PV. 33 Two case reports have described individuals with treatment-resistant PG and PV who carried the JAK2 V617F mutation. 35,36 Furthermore, successful treatment of PG using JAK inhibitors in patients without PV have been reported, indicating a potential role of the JAK-STAT pathway in PG pathogenesis.…”

“…33 Janus kinase 2 (JAK2) is a crucial protein involved in the JAK-signal transducer and activator of transcription (STAT) pathway, which also mediates G-CSF receptor signaling. 33 Enhanced JAK2 V617F signal transduction leads to abnormal overproduction of neutrophils, red blood cells, and platelets in individuals with PV. 33 Two case reports have described individuals with treatment-resistant PG and PV who carried the JAK2 V617F mutation.…”

Proof of concept of triple COMBI therapy to prohibit MPN progression to AML

“…2 These beneficial IFN effects are only obtained if treatment is instituted at the earliest MPN stages-ET and PV, whereas patients in the advanced myelofibrosis stage with severe bone marrow fibrosis and huge splenomegaly have no or minor benefit of IFN treatment. Unfortunately, 20%-40% of MPN patients do not tolerate IFN or are refractory to treatment in terms of no or only minor reduction in the JAK2V617F mutational load with a concomitant risk of thrombosis and accelerated atherosclerosis, since the JAK2V617F mutation per se is potently inflammatory and thrombogenic 4,5 even in the CHIP stage. 6 The reasons for intolerance and/or refractoriness to IFN are several but may be explained by a large 'tumour burden', additive mutations and excessive chronic inflammation.…”