Whole blood transcriptional profiling reveals deregulation of oxidative and antioxidative defence genes in myelofibrosis and related neoplasms. Potential implications of downregulation of Nrf2 for genomic instability and disease progression

• Published in: PloS one Vol. 9; no. 11; p. e112786
• Main Authors: Hasselbalch, Hans Carl, Thomassen, Mads, Riley, Caroline Hasselbalch, Kjær, Lasse, Larsen, Thomas Stauffer, Jensen, Morten K, Bjerrum, Ole Weis, Kruse, Torben A, Skov, Vibe
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14-11-2014; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Antigens; Biology and Life Sciences; Blood; Blood cancer; Blood Proteins - metabolism; Cancer; Cancer genetics; Cell migration; CXCR4 protein; Datasets; Denmark; Deoxyribonucleic acid; Deregulation; Development and progression; Disease; Disease Progression; DNA; DNA methylation; Female; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - physiology; Genes; Genetic aspects; Genomic instability; Genomic Instability - genetics; Genomic Instability - physiology; Hematology; Hematopoietic stem cells; Humans; Hypothesis testing; Inflammation; Lymphoma; Lymphomas; Male; Medicine and Health Sciences; Middle Aged; Mitochondrial uncoupling protein 2; Mutation; Myelofibrosis; Myeloproliferative Disorders - metabolism; Neoplasms; NF-E2-Related Factor 2 - metabolism; NRF2 protein; Oxidative stress; Oxygen; Patients; Polycythemia; Polycythemia vera; Profiling; Reactive oxygen species; Receptors, CXCR4 - metabolism; Stability; Stem cells; Transcription (Genetics); Tumors; Denmark
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0112786

The Philadelphia-negative chronic myeloproliferative neoplasms - essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) (MPNs) - have recently been shown to be associated with chronic inflammation, oxidative stress and accumulation of reactive oxygen species (ROS). Using whole blood transcriptional profiling, we report that several oxidative stress and anti-oxidative stress genes are significantly deregulated in MPNs. Among the twenty most up- and downregulated genes, ATOX1, DEFB122, GPX8, PRDX2, PRDX6, PTGS1, and SEPP1 were progressively upregulated from ET over PV to PMF, whereas AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively downregulated in ET, PV and PMF (all FDR <0.05). The gene Nrf2, encoding the transcription factor nuclear factor erythroid 2-related factor 2 (NFE2L2 or Nrf2) was significantly downregulated in all MPNs. Nrf2 has a key role in the regulation of the oxidative stress response and modulates both migration and retention of hematopoietic stem cells (HSCs) in their niche. The patogenetic importance of Nrf2 depletion in the context of expansion of the hematopoietic progenitor pool in MPNs is discussed with particular focus upon the implications of concomitant downregulation of Nrf2 and CXCR4 for stem cell mobilization.