JAK2V617F Allele Burden in Polycythemia Vera: Burden of Proof

[Manouche]

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 JAK2V617FVAF as a diagnostic and prognostic biomarker, and utility of JAK2V617F VAF reduction in PV treatment »

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[MPort]

Many thanks for this concise explanation. It helps me understand PV and will be useful to explain it to others.

[monarch5000]

$100.00 to access the article.

[Manouche]

 »…Moreover, in the interferon contexts, deeper molecular responses associate with longer disease remissions after discontinuation of therapy. It remains to be seen whether deeper molecular responses in PV exert a more profound impact on disease progression, apropos of chronic myeloid leukemia treatment. This is an area of active study, with recent investigations reported on the clinical basis of variation in interferon response and pathways that potentiate the susceptibility of JAK2V617F-mutant stem cells to interferon therapy, and trials that target PV earlier in disease course. Outstanding questions also center on degree of VAF reduction to mitigate thrombosis risk, how closely peripheral VAF suppression reflects clonal suppression of JAK2 mutated stem cells, when to initiate therapy, and durability of clonal suppression after achieving VAF reductions.

Conclusions

The JAK2V617F discovery has elucidated the basis of the quantity of blood cell production, the unique qualities of JAK2V617F cells, and the clonal expansion dynamics of JAK2V617F HSCs in PV. Physicians and their patients can apply the knowledge of JAK2V617F VAF to understanding that risk is defined not by blood counts alone but on the intrinsic effects of JAK2V617F VAF that impart risk to both thrombosis and disease progression. The meaning of VAF reduction in PV is emerging through the analysis of prospective randomized trials where VAF was correlated with response and outcomes, and proof is mounting that reduction of VAF is tied to not only blood count control, but also thrombosis risk reduction and disease progression reduction. Taken together, PV treatments that do not address clonal expansion of JAK2V617F and therefore do not reduce JAK2V617F VAF do not optimally address thrombosis or disease progression risk, and represent missed opportunities for our patients to receive disease modifying therapies. PV therapy, like CML therapy, requires years of exposure to achieve molecular responses, and thus off target effects, tolerability, immune suppression and cancer development are additional major concerns and challenges. Long term exposure to agents that place JAK2V617F HSCs under a selection stress without ultimate clonal suppression, translate to selection for mutational events that drive progression or AML. pathophysiology has yielded many new candidates to target clonal expansion in PV.

Therapies that upregulate hepcidin, suppress key inflammatory signaling pathways, activate p53, inhibit HIF95, target DNA repair pathways or facilitate JAK2V617F stem cell extinction are exciting developments for PV. »

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