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Ref Type Journal Article
PMID (30287855)
Authors Verger E, Soret-Dulphy J, Maslah N, Roy L, Rey J, Ghrieb Z, Kralovics R, Gisslinger H, Grohmann-Izay B, Klade C, Chomienne C, Giraudier S, Cassinat B, Kiladjian JJ
Title Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo.
Journal Blood cancer journal
Vol 8
Issue 10
Date 2018 10 04
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Ropeginterferon Ropeginterferon 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Ropeginterferon RopegInterferon alpha-2b|Ropeg|Besremi Ropeginterferon is polyethylene glycol (PEG)-conjugated recombinant interferon alpha, subtype 2b, which may result in reduced tumor cell proliferation and colony growth (PMID: 30287855).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
DNMT3A S837* nonsense unknown DNMT3A S837* results in a premature truncation of the Dnmt3a protein at amino acid 837 of 912 (UniProt.org). S837* has been identified in the scientific literature (PMID: 30287855), but has not been biochemically characterized and therefore, its effect on Dnmt3a protein function is unknown (PubMed, Jul 2021).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 V617F polycythemia vera sensitive Ropeginterferon Clinical Study - Cohort Actionable In a clinical study using data from a Phase III trial, polycythemia vera patients demonstrated significant reduction in the median JAK2 V617F mutational burden at 12 months following treatment with Ropeginterferon compared to Droxia (hydroxyurea) (13.8% vs. 33.2%; p<0.02) (PMID: 30287855; NCT01949805). 30287855
JAK2 V617F acute megakaryocytic leukemia sensitive Ropeginterferon Preclinical - Cell culture Actionable In a preclinical study, a megakaryoblastic leukemia cell line expressing JAK2 V617F demonstrated inhibition of cell proliferation in culture when treated with Ropeginterferon (PMID: 30287855). 30287855
JAK2 V617F polycythemia vera sensitive Ropeginterferon Preclinical - Patient cell culture Actionable In a preclinical study, patient-derived erythroid progenitors harboring JAK2 V617F demonstrated sensitivity to Ropeginterferon in culture (PMID: 30287855). 30287855
JAK2 V617F myeloproliferative neoplasm sensitive Ropeginterferon Preclinical - Cell culture Actionable In a preclinical study, Ropeginterferon treatment resulted in dose-dependent inhibition of cell proliferation in myeloproliferative neoplasm cell lines harboring JAK2 V617F in culture (PMID: 30287855). 30287855