Pegylated interferon alfa (pegIFN-α) can induce molecular remissions in patients with JAK2-V617F-positive myeloproliferative neoplasms (MPNs) by targeting long-term hematopoietic stem cells (LT-HSCs). Additional somatic mutations in genes regulating LT-HSC self-renewal, such as DNMT3A, have been reported to have poorer responses to pegIFN-α. We investigated whether DNMT3A loss leads to alterations in JAK2-V617F LT-HSC functions conferring resistance to pegIFN-α treatment in a mouse model of MPN and in hematopoietic progenitors from patients with MPN. Long-term treatment with pegIFN-α normalized blood parameters and reduced splenomegaly and JAK2-V617F chimerism in single-mutant JAK2-V617F (VF) mice. However, pegIFN-α in VF;Dnmt3aΔ/Δ (VF;DmΔ/Δ) mice worsened splenomegaly and failed to reduce JAK2-V617F chimerism. Furthermore, LT-HSCs from VF;DmΔ/Δ mice compared with VF were less prone to accumulate DNA damage and exit dormancy upon pegIFN-α treatment. RNA sequencing showed that IFN-α induced stronger upregulation of inflammatory pathways in LT-HSCs from VF;DmΔ/Δ than from VF mice, indicating that the resistance of VF;DmΔ/Δ LT-HSC was not due to failure in IFN-α signaling. Transplantations of bone marrow from pegIFN-α-treated VF;DmΔ/Δ mice gave rise to more aggressive disease in secondary and tertiary recipients. Liquid cultures of hematopoietic progenitors from patients with MPN with JAK2-V617F and DNMT3A mutation showed increased percentages of JAK2-V617F-positive colonies upon IFN-α exposure, whereas in patients with JAK2-V617F alone, the percentages of JAK2-V617F-positive colonies decreased or remained unchanged. PegIFN-α combined with 5-azacytidine only partially overcame resistance in VF;DmΔ/Δ mice. However, this combination strongly decreased the JAK2-mutant allele burden in mice carrying VF mutation only, showing potential to inflict substantial damage preferentially to the JAK2-mutant clone.

• MeSH
• buněčná sebeobnova MeSH
• chemorezistence * genetika   MeSH
• DNA methyltransferasa 3A * genetika   MeSH
• DNA-(cytosin-5-)methyltransferasa * genetika   metabolismus   MeSH
• hematopoetické kmenové buňky * metabolismus   patologie   účinky léků   MeSH
• interferon alfa * farmakologie   MeSH
• Janus kinasa 2 * genetika   metabolismus   MeSH
• lidé MeSH
• myeloproliferativní poruchy * genetika   patologie   farmakoterapie   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• polyethylenglykoly farmakologie   MeSH
• rekombinantní proteiny MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA methyltransferasa 3A * MeSH
• DNA-(cytosin-5-)methyltransferasa * MeSH
• DNMT3A protein, human MeSH Prohlížeč
• Dnmt3a protein, mouse MeSH Prohlížeč
• interferon alfa * MeSH
• JAK2 protein, human MeSH Prohlížeč
• Jak2 protein, mouse MeSH Prohlížeč
• Janus kinasa 2 * MeSH
• peginterferon alfa-2a MeSH Prohlížeč
• polyethylenglykoly MeSH
• rekombinantní proteiny MeSH

• Publikační typ
• časopisecké články MeSH

In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) α-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients. The main goal was to define the maximum tolerated dose and to assess safety and efficacy. A dose range of 50 to 540 µg was tested without the appearance of dose-limiting toxicities. All drug-related adverse events were known toxicities associated with IFN-α. The cumulative overall response rate was 90%, comprising complete response in 47% and partial response in 43% of patients; the best individual molecular response level was a complete response in 21% of patients and partial response in 47%. Notably, we did not observe any correlation between the dose level and the response rate or response duration, suggesting that already low levels of ropeginterferon alfa-2b are sufficient to induce significant hematologic and molecular responses. These data suggest promising efficacy and safety of ropeginterferon alfa-2b and support the development of the drug in a randomized phase 3 clinical trial. The study was disclosed at www.clinicaltrials.gov as #NCT01193699 before including the first patient.

• MeSH
• dospělí MeSH
• indukce remise MeSH
• interferon alfa-2 MeSH
• interferon alfa terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• maximální tolerovaná dávka MeSH
• míra přežití MeSH
• následné studie MeSH
• poločas MeSH
• polycythaemia vera farmakoterapie   mortalita   patologie   MeSH
• polyethylenglykoly chemie   MeSH
• prognóza MeSH
• rekombinantní proteiny terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• Názvy látek
• interferon alfa-2 MeSH
• interferon alfa MeSH
• polyethylenglykoly MeSH
• rekombinantní proteiny MeSH