Interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms favorably impacts deregulation of oxidative stress genes and antioxidative defense mechanisms

• Published in: PloS one 2022-06, Vol.17 (6), p.e0270669-e0270669
• Main Authors: Skov, Vibe, Thomassen, Mads, Kjær, Lasse, Ellervik, Christina, Larsen, Morten Kranker, Knudsen, Trine Alma, Kruse, Torben A, Hasselbalch, Hans C
• Format: Article
• Language: English
• Subjects: Analysis; Biological response modifiers; Biology and Life Sciences; Blood; Blood cancer; Bone marrow; Care and treatment; Cell cycle; Cellular stress response; CXCR4 protein; Datasets; Deregulation; Disease; Evolution; Gene expression; Genes; Genomic instability; Genotoxicity; Health aspects; Hematopoietic stem cells; Hypotheses; Hypothesis testing; Inflammation; Interferon; Interferon alpha; Leukemia; Medicine and Health Sciences; Mutation; Myelofibrosis; Neoplasms; Oxidative stress; Oxygen; p53 Protein; Patients; Physical Sciences; Polycythemia; Polycythemia vera; Reactive oxygen species; Spleen; Stem cells; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0270669

Chronic inflammation is considered a major driving force for clonal expansion and evolution in the Philadelphia-negative myeloproliferative neoplasms, which include essential thrombocythemia, polycythemia vera and primary myelofibrosis (MPNs). One of the key mutation drivers is the JAK2V617F mutation, which has been shown to induce the generation of reactive oxygen species (ROS). Using whole blood gene expression profiling, deregulation of several oxidative stress and anti-oxidative defense genes has been identified in MPNs, including significant downregulation of TP53, the NFE2L2 or NRF2 genes. These genes have a major role for maintaining genomic stability, regulation of the oxidative stress response and in modulating migration or retention of hematopoietic stem cells. Therefore, their deregulation might give rise to increasing genomic instability, increased chronic inflammation and disease progression with egress of hematopoietic stem cells from the bone marrow to seed in the spleen, liver and elsewhere. Interferon-alpha2 (rIFN[alpha]) is increasingly being recognized as the drug of choice for the treatment of patients with MPNs. Herein, we report the first gene expression profiling study on the impact of rIFN[alpha] upon oxidative stress and antioxidative defense genes in patients with MPNs (n = 33), showing that rIFN[alpha] downregulates several upregulated oxidative stress genes and upregulates downregulated antioxidative defense genes. Treatment with rIFN[alpha] induced upregulation of 19 genes in ET and 29 genes in PV including CXCR4 and TP53. In conclusion, this rIFN[alpha]- mediated dampening of genotoxic damage to hematopoietic cells may ultimately diminish the risk of additional mutations and accordingly clonal evolution and disease progression towards myelofibrotic and leukemic transformation.