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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.

Hasselbalch HC, Thomassen M, Riley CH, Kjær L, Larsen TS, Jensen MK, Bjerrum OW, Kruse TA, Skov V - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark.

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.

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Related in: MedlinePlus

AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively and significantly downregulated in patients with ET, PV, and PMF (FDR <0.05).Fold changes for each gene are shown on the y-axis.
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pone-0112786-g002: AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively and significantly downregulated in patients with ET, PV, and PMF (FDR <0.05).Fold changes for each gene are shown on the y-axis.

Mentions: In data set 1, 20,439, 25,307, and 17,417 probe sets were identified to be differentially expressed between controls and patients with ET, PV, and PMF, respectively (FDR <0.05). 148 of these genes were found to be included in previous studies focusing on deregulation of oxidative stress genes in various diseases and were chosen for further analysis (Table S1). 35, 40, and 46 oxidative stress genes were significantly upregulated and 33, 37, and 23 were significantly downregulated in patients with ET, PV, and PMF, respectively. The twenty most up- and downregulated genes are shown in Table 4 and Table 5, respectively. ATOX1, DEFB122, GPX8, PRDX2, PRDX6, PTGS1, and SEPP1 were progressively upregulated from ET over PV to PMF (Figure 1), whereas AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively downregulated in ET, PV and PMF (Figure 2) (all FDR <0.05). Since inactivation of certain genes - e.g. FoxO3, TP53 and ATM - are associated with increased ROS levels and impairment of hematopoietic stem cell function, the expression of these genes was included as well. The FoxO1 gene was significantly downregulated in PV: (Fold Change (FC)  = −1.22; FDR  = 0.01) and PMF: (FC  = −2.0; FDR  = 4.4E-06). The FoxO3 gene was significantly upregulated in PV: FC  = 1.6, FDR  = 6.3E-05 and PMF: FC  = 1.7, FDR  = 0.008). The TP53 gene was highly significantly downregulated in ET, PV and PMF: (FC −1.5, −1.5 and −1.5, respectively; FDR  = 2.6E-07, 2.6E-14, and 3.4E-05, respectively. The ATM gene was significantly and progressively downregulated in ET, PV and PMF: (ET: FC = −1.3; FDR  = 0.0006; PV: FC  = −1.3, FDR  = 2.3E-06; PMF: FC  = −1.5, FDR  = 0.0002). CCND1 was highly significantly upregulated in ET, PV and PMF: FC  = 1.3, 1.3, 1.9, respectively; FDR  = 8.9E-06, 2.9E-06, 0.009, respectively; and CXCR4 was highly significantly downregulated in ET, PV and PMF: FC  = −2.1, −2.0, −2.8, respectively; FDR  = 3.7E-09, 1.1E-11, 1.5E-09, respectively. No significant differences in white blood cell counts and differential counts were recorded between the three subgroups of patients (Table 2). The 20 most up- and downregulated genes from data set 1 are evaluated in data set 2 and shown in Table 4 and 5, respectively.


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.

Hasselbalch HC, Thomassen M, Riley CH, Kjær L, Larsen TS, Jensen MK, Bjerrum OW, Kruse TA, Skov V - PLoS ONE (2014)

AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively and significantly downregulated in patients with ET, PV, and PMF (FDR <0.05).Fold changes for each gene are shown on the y-axis.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4232509&req=5

pone-0112786-g002: AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively and significantly downregulated in patients with ET, PV, and PMF (FDR <0.05).Fold changes for each gene are shown on the y-axis.
Mentions: In data set 1, 20,439, 25,307, and 17,417 probe sets were identified to be differentially expressed between controls and patients with ET, PV, and PMF, respectively (FDR <0.05). 148 of these genes were found to be included in previous studies focusing on deregulation of oxidative stress genes in various diseases and were chosen for further analysis (Table S1). 35, 40, and 46 oxidative stress genes were significantly upregulated and 33, 37, and 23 were significantly downregulated in patients with ET, PV, and PMF, respectively. The twenty most up- and downregulated genes are shown in Table 4 and Table 5, respectively. ATOX1, DEFB122, GPX8, PRDX2, PRDX6, PTGS1, and SEPP1 were progressively upregulated from ET over PV to PMF (Figure 1), whereas AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively downregulated in ET, PV and PMF (Figure 2) (all FDR <0.05). Since inactivation of certain genes - e.g. FoxO3, TP53 and ATM - are associated with increased ROS levels and impairment of hematopoietic stem cell function, the expression of these genes was included as well. The FoxO1 gene was significantly downregulated in PV: (Fold Change (FC)  = −1.22; FDR  = 0.01) and PMF: (FC  = −2.0; FDR  = 4.4E-06). The FoxO3 gene was significantly upregulated in PV: FC  = 1.6, FDR  = 6.3E-05 and PMF: FC  = 1.7, FDR  = 0.008). The TP53 gene was highly significantly downregulated in ET, PV and PMF: (FC −1.5, −1.5 and −1.5, respectively; FDR  = 2.6E-07, 2.6E-14, and 3.4E-05, respectively. The ATM gene was significantly and progressively downregulated in ET, PV and PMF: (ET: FC = −1.3; FDR  = 0.0006; PV: FC  = −1.3, FDR  = 2.3E-06; PMF: FC  = −1.5, FDR  = 0.0002). CCND1 was highly significantly upregulated in ET, PV and PMF: FC  = 1.3, 1.3, 1.9, respectively; FDR  = 8.9E-06, 2.9E-06, 0.009, respectively; and CXCR4 was highly significantly downregulated in ET, PV and PMF: FC  = −2.1, −2.0, −2.8, respectively; FDR  = 3.7E-09, 1.1E-11, 1.5E-09, respectively. No significant differences in white blood cell counts and differential counts were recorded between the three subgroups of patients (Table 2). The 20 most up- and downregulated genes from data set 1 are evaluated in data set 2 and shown in Table 4 and 5, respectively.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark.

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.

Show MeSH
Related in: MedlinePlus