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

Abstract

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.

Perspectives on interferon-alpha in the treatment of polycythemia vera and related myeloproliferative neoplasms: minimal residual disease and cure?

“…In this regard, we have also by transcriptional profiling studies described a marked deregulation of oxidative and antioxidative stress genes [112], supporting the concept of chronic inflammation as the driving force for clonal evolution in MPNs. Most recently, our mathematical modeling studies have also delivered the proof of concept for MPNs as a human inflammation model for cancer development [113].…”

Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

“…In this regard, an analysis of the antioxidant defense pathway-gene expression array using RNA from wild type and NRF2-null mice tissue, revealed that the expression of GPX8 was down-regulated in the absence of NRF2 [60]. In line with this, transcriptome analysis from patient samples suffering from myeloproliferative neoplasms, polycythemia or myelofibrosis, diseases also associate with oxidative stress and low-grade chronic inflammation, show lower expression levels of both NRF2 and GPX8 compared with control subjects [61]. There are not yet studies that specifically involve GPX8 in human brain protection but a transcriptome analysis in mice indicates a compensatory GPX8 increase in response to the Parkinsonian toxin MPTP [62].…”

A 7-Gene Signature Depicts the Biochemical Profile of Early Prefibrotic Myelofibrosis

“…The egress of CD34+ cells from the stem cell niches into the circulation has been compared to the metastatic process in solid tumors [49], in which a large number of chemokines, cytokines and proteolytic enzymes are deeply involved [23–26, 50–53]. In this process–as well as in the progression of myelofibrosis from early cancer stage to the advanced cancer stage (MMM)–inflammation and immune deregulation is today considered of major importance [21–23, 53–57].…”