Abstract
Polycythemia vera is characterized by the acquisition of the JAK2V617F mutation. Recommended treatments include hydroxyurea and interferon-alpha. Several groups have reported a reduction in the JAK2 mutant allele burden in interferon-treated patients, but significance of this observation is questioned. We characterized the activity of ropeginterferon alpha-2b, a novel form of interferon-alpha recently shown to be safe and efficacious in polycythemia vera. Ropeginterferon was able to inhibit the proliferation of the HEL, UKE-1, and UT-7 JAK2-mutant cell lines while sparing JAK2-wild-type UT-7 and normal CD34+ cells growth. In vitro treatment of erythroid progenitors derived from PV patients showed that ropeginterferon could considerably inhibit the growth of endogenous erythroid colonies, a hallmark of polycythemia vera. Finally, we could study in sequential samples the clonal architecture of erythroid progenitors derived from patients included in a randomized study comparing hydroxyurea to ropeginterferon. After 1 year of treatment with ropeginterferon, the ratio of JAK2-mutated to wild-type colonies grown from bone marrow progenitors was reduced by 64%, compared to 25% in patients receiving hydroxyurea. This study shows that ropeginterferon has a potent targeted activity against JAK2-mutant cells and is able to drastically reduce the proportion of malignant progenitors in patients treated with this drug.
Highlights
Polycythemia vera is characterized by the acquisition of the JAK2V617F mutation
We could assess the impact of HU and Ropeg treatments in vivo by sequential studies of bone marrow (BM) progenitors of Polycythemia vera (PV) patients treated for 12 months with both drugs in a prospective, randomized study
To test for a more-specific action of Ropeg against the JAK2V617F mutant form compared to JAK2 wild type, we used the UT-7 model in which both forms of the JAK2 gene have been transduced
Summary
Polycythemia vera is characterized by the acquisition of the JAK2V617F mutation. Recommended treatments include hydroxyurea and interferon-alpha. This study shows that ropeginterferon has a potent targeted activity against JAK2-mutant cells and is able to drastically reduce the proportion of malignant progenitors in patients treated with this drug. We and discovered, including mutations in genes affecting the epigenome (TET2, ASXL1, DNMT3a, or EZH2), or contributing to transformation to acute leukemia (NRAS, KRAS, TP53, or IDH1/2)[2,3] The presence of such others have observed significant reductions of the JAK2V617F allele burden (%JAK2V617F) in IFNα-treated patients[11,12] suggesting that IFNα is able to target the malignant clone. We characterized Ropeg activity against JAK2V617F mutated cells We tested this new drug in vitro against JAK2-mutant and wild-type cell lines and patients’ primary cells. We could assess the impact of HU and Ropeg treatments in vivo by sequential studies of bone marrow (BM) progenitors of PV patients treated for 12 months with both drugs in a prospective, randomized study
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