Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia

Wu, Runpei; Hayashi, Tomoko; Cottam, Howard B.; Jin, Guangyi; Yao, Shiyin; Wu, Christina; Rosenbach, Michael; Corr, Maripat; Schwab, Richard B.; Carson, Dennis A.

doi:10.1073/pnas.1002890107

Cited by 115 publications

(98 citation statements)

References 32 publications

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“…An immunodominant T-helper peptide from the outer membrane protein P6 (18) was used to measure the frequency of cytokine secreting antigen-specific T-cells in the lymphoid organs of WT and Nrf2 2/2 mice exposed to NTHI (Figure 4). T-cells from the spleens and draining lymph nodes (cervical) of both genotypes were capable of secreting the cytokines IL-2, IFN-g, IL-4, and IL-17 in response to 18 hours of stimulation with the P6 [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] peptide. This suggests that there was no bias in the cytokine profile of the T-cells from the lymphoid organs of WT or Nrf2 2/2 mice as they secreted the signature cytokines of the Th1, Th2, and Th17 subsets.…”

Section: Enhanced Lymphocytic Airway Inflammation In Lungs Of Nrf2 2/mentioning

confidence: 99%

“…Lymphocytes were cocultured with syngeneic antigen-presenting cells (APCs) pulsed with 1 mM P6 [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] peptide from the outer membrane protein P6 of NTHI. After an 18-hour culture, the plates were washed extensively, and cytokines were detected with biotinylated antibodies followed by addition of streptavidin-HRP.…”

Section: Cytokine Elispotsmentioning

confidence: 99%

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Nrf2 Regulates Chronic Lung Inflammation and B-Cell Responses to Nontypeable Haemophilus influenzae

Lugade

Vethanayagam

Nasirikenari

et al. 2011

Am J Respir Cell Mol Biol

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Nrf2 is a leucine zipper transcription factor that protects against oxidant-induced injury. Nontypeable Haemophilus influenzae is responsible for frequent disease exacerbations in patients with chronic obstructive pulmonary disease and is responsible for causing otitis media in young children. We hypothesized that Nrf2 would limit inflammatory responses to nontypeable H. influenzae. The objective of this study was to assess the role of Nrf2 in chronic lung inflammation and regulation of immune responses to nontypeable H. influenzae in mice. Wild-type (C57BL/6) mice and Nrf2 2/2 mice were instilled by oropharyngeal aspiration of 1 3 10 6 colony-forming units of live, nontypeable H. influenzae (NTHI) twice a week for 4 to 16 consecutive weeks to generate a chronic inflammatory milieu within the lungs that models chronic bronchitis. Nrf2 2/2 mice had increased lymphocytic airway inflammation compared with WT mice after NTHI challenge. Although the extent of NTHI-induced peribronchovascular inflammation did not significantly differ between the genotypes, plasma cell infiltration was significantly more abundant in Nrf2 2/2 mice. Most strikingly, Nrf2 2/2 mice generated significantly enhanced and persistent levels of serum antibodies against P6, a key outer membrane protein of NTHI. Lung dendritic cells from Nrf2 2/2 mice challenged with NTHI had increased activation markers compared with dendritic cells from similarly treated WT mice. Nrf2 regulates NTHI-induced airway inflammation characterized by lymphocytic and plasma cell infiltration and the activation of lung dendritic cells and B-cell responses in mice. Nrf2 may be a potential therapeutic target in limiting the bacterial infectioninduced airway inflammation that drives exacerbations of chronic obstructive pulmonary disease.

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Section: Enhanced Lymphocytic Airway Inflammation In Lungs Of Nrf2 2/mentioning

confidence: 99%

Section: Cytokine Elispotsmentioning

confidence: 99%

Nrf2 Regulates Chronic Lung Inflammation and B-Cell Responses to Nontypeable Haemophilus influenzae

Lugade

Vethanayagam

Nasirikenari

et al. 2011

Am J Respir Cell Mol Biol

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“…Previous reports have demonstrated increased sensitivity of CLL cells to pro-oxidant based therapies compared to nontumor cells, but this is the first study to demonstrate that this approach specifically targets the ATM-null phenotype in CLL. 34,35 Our data suggest that binding of NRF2 to target gene AREs is reduced in ATM-null CLL despite normal levels of NRF2, KEAP1, BACH1 and MAF proteins and normal levels of NRF2/MAF heterodimerization. Previous studies indicated that reduced PKCδ levels might contribute to defective Nrf-2 regulation in Atm-/-mice and that NRF2 stability is regulated by phosphorylation at ser40 by PKC.…”

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confidence: 90%

Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o n(ROS) production or reduced antioxidant capacity. A principle antioxidant pathway is regulated by the redox sensitive transcription factor, NF-E2 p45-related factor-2 (NRF2/NFE2L2). In unstressed cells, low levels of NRF2 are maintained through interaction with Kelch-like ECHassociated protein 1 (KEAP1), an adapter for the E3 ubiquitin ligase Cullin 3 (CUL3) that directs NRF2 for proteasomal degradation. 13 Modification of redox and electrophile sensitive cysteine residues inhibits the substrate adaptor activity of KEAP1 allowing NRF2 accumulation. The interaction of KEAP1 with NRF2 is further modulated by phosphorylation of NRF2 at serine 40 by protein kinase C (PKC).14 Within the nucleus, NRF2 forms heterodimers with v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF) proteins (MAF-F, G and K) and binds to antioxidant response elements (AREs) in the promoters of target genes such as those required for glutathione synthesis and its own promoter. 15 This activity is regulated by the transcriptional repressor BTB and CNC homology 1 transcription factor (BACH1) which competes for the MAF binding partners and for binding to gene promoters. 16 In addition, genetic models suggest that binding of Nrf-2 and its activity are regulated by the ATM substrate, Brca1. 17The most compelling evidence for the role of ATM in redox homeostasis comes from studies of the human radiosensitivity syndrome, Ataxia Telangiectasia (A-T), where both ATM alleles are inactivated. Cells from these patients display increased oxidative stress as a consequence of elevated levels of ROS, increased oxidized/reduced glutathione (GSSG/GSH) ratio, diminished capacity to scavenge ROS and mitochondrial dysfunction. 12,18 Furthermore, ATM is directly activated by oxidative stress 19 and can exert antioxidant activity through regulation of the pentose-phosphate pathway. 20 Recent evidence suggests that ATM might regulate oxidative stress through NRF2. Namely, Nrf2 target gene expression was decreased in Atm-/-murine osteoblasts and this was rescued by the ectopic expression of PKC delta (PKCδ). 21 In this study, we tested the hypothesis that ATM-null CLLs have an intrinsic defect in their antioxidant defenses that might be exploited to induce synthetic lethality of tumor cells by escalating oxidative stress. We show that compared to ATM-wild type (wt) CLL, ATM-null CLL tumors exhibited defective NRF2-dependent antioxidant transcriptional responses, decreased antioxidant capacity, elevated mitochondrial ROS, and increased sensitivity to pro-oxidants both in vitro and in vivo. Furthermore, we demonstrate that pro-oxidant treatment bypassed the need for a functional DRR and induced cell death via a p53-and caspase-independent mechanism involving apoptosis inducing factor (AIF). Methods Patients' samples and cell linesChronic lymphocytic leukemia samples were obtained from Birmingham and Bournemouth Hospitals (Online Supplementary Table S1). These were comprised of 3 CLLs with monoallelic ATM...

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“…In a previous study of 43 AML patients, 33 expressed high levels of HO-1 (77%) (5). In addition, higher levels of HO-1 are expressed in chronic lymphocytic leukemia (CLL) cells compared with normal lymphocytes (6). In a previous study, inducing high expression of HO-1 gene increased the expression of multidrug-resistance gene, accompanied by elevated IC 50 values in a number of types of tumor cells (7).…”

Section: Introductionmentioning

confidence: 99%

HO-1, RET and PML as possible markers for risk stratification of acute myelocytic leukemia and prognostic evaluation

Wang

et al. 2015

Oncology Letters

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Abstract. Heme oxygenase-1 (HO-1) is an inducible isoform of HO that is activated in response to oxidative stress and has anti-apoptotic and pro-proliferative effects on leukemia cells. RET, a tyrosine kinase receptor; its expression levels are associated with the differentiation degree of acute myelocytic leukemia (AML) cells. The promyelocytic leukemia (PML) gene inhibits cell proliferation and tumor growth, participates in the differentiation of hematopoietic progenitor cells and induces cell apoptosis. However, the association between the expression levels of HO-1, RET and PML genes and the risk stratification of AML and prognosis have not previously been reported. In the present study, HO-1 was expressed in the human AML Kasumi-1, HL-60 and THP-1 cell lines, and HO-1 expression was regulated by Hemin (20 µmol/l) and ZnPPIX (10 µmol/l). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis demonstrated that expression of RET and PML were positively and negatively correlated with HO-1 expression, respectively. Bone marrow samples (18 favorable, 55 intermediate, 15 adverse and 2 unknown karyotype AML cases and 20 healthy donors) were collected from 90 randomly selected AML patients upon their first visit. The mRNA and protein expression of HO-1, RET and PML in samples was detected by RT-qPCR and western blot analysis. At the mRNA level, the adverse group expressed significantly higher levels of HO-1 and RET compared with the levels in the favorable and normal groups. The PML mRNA expression levels in adverse patient samples was lower compared with those of the intermediate group and favorable group. Western blot analysis demonstrated that the expression levels of HO-1, RET and PML proteins in all risk groups exhibited the same pattern of expression as was observed for the mRNA levels. The overall survival and relapse-free survival rates were shortest in AML patients with high HO-1 expression (Kaplan-Meier; log-rank, P<0.01). The results of the present study therefore indicate that HO-1, RET and PML may be critical in the risk-stratification and prognosis of AML. However, additional samples and clinical data should be collected and analyzed in order to provide stronger evidence for this hypothesis.

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Nrf2 responses and the therapeutic selectivity of electrophilic compounds in chronic lymphocytic leukemia

Cited by 115 publications

References 32 publications

Nrf2 Regulates Chronic Lung Inflammation and B-Cell Responses to Nontypeable Haemophilus influenzae

Nrf2 Regulates Chronic Lung Inflammation and B-Cell Responses to Nontypeable Haemophilus influenzae

Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants

HO-1, RET and PML as possible markers for risk stratification of acute myelocytic leukemia and prognostic evaluation

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