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.
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.
Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark.
Hans Carl
HC
Hasselbalch
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Mads
M
Thomassen
Department of Hematology L, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
Caroline Hasselbalch
CH
Riley
Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark.
Lasse
L
Kjær
Department of Hematology X, Odense University Hospital, Odense, Denmark.
Thomas Stauffer
TS
Larsen
Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark.
Morten K
MK
Jensen
Department of Hematology L, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Ole Weis
OW
Bjerrum
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Torben A
TA
Kruse
Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark.
Vibe
V
Skov
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001798:Blood Proteins / Q000378:metabolism*; D003718:Denmark; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D042822:Genomic Instability / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*
D001798:Blood Proteins; C527276:CXCR4 protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D019718:Receptors, CXCR4