NFE2L2,KEAP1AND NQO1GENE EXPRESSION IN MYELODYSPLASTIC SYNDROME AND MONOCLONAL GAMMOPATHIES? CLINICAL IMPLICATIONS
(Abstract release date: 05/19/16)
EHA Library. Bela Sarmento-Ribeiro A. 06/09/16; 134823; PB1923
Ana Bela Sarmento-Ribeiro
Contributions
Contributions
Abstract
Abstract: PB1923
Type: Publication Only
Background
Oxidative stress (OS) deregulation has been associated with almost all neoplastic diseases, including leukemia, where it contributes to disease development and progression. NRF2 (Nuclear factor erythroid-2-related factor 2) is a transcription factor codified by NFE2L2 gene (Nuclear factor erythroid2-like 2) that activate many antioxidant and detoxification genes, like the NQO1 (NAD(P)H:quinone oxidoreductase 1) gene, through its binding to antioxidant response element (ARE) and regulate ARE-mediated gene expression and induction. Moreover, NRF2 is strongly regulated by KEAP1 (Kelch-like ECH-associated protein 1). NRF2-KEAP1 system seems to have an extremely important role in OS regulation, contributing for disease development and/or influence therapy response.
Aims
Our aim was to evaluate the expression levels of NFE2L2, KEAP1 and NQO1 genes in Myelodysplastic Syndrome (MDS) and Monoclonal Gammopathies (MG) patients, and its correlation with clinical and laboratorial data, in order to identify potential biomarkers of diagnosis and/or prognosis.
Methods
We evaluated 135 samples, 53 MDS (26 refractory cytopenia with multilineage dysplasia; 8 chronic myelomonocytic leukemia; 7 refractory cytopenia with unilineage dysplasia; 5 refractory anemia with excess blasts-1; 4 refractory anemia with ringed sideroblasts; 2 refractory anemia with excess blasts-2; 1 5q-), 40 MG (15 monoclonal gammopathies of undetermined significance; 25 multiple myeloma) and 42 controls (Ctl). Samples were collected after informed consent obtained in accordance with the Helsinki Declaration. Real-time PCR was used to evaluate the gene expression level of NFE2L2, KEAP1, NQO1 andGUS (control gene). Results were considered statistically significant when p<0,05.
Results
Our results showed that patient´s group presents higher KEAP1 expression levels comparing to controls (Patients: 0,175; CTL: 0,097; p=0,04), while NFE2L2did not presented differences between any groups. When we analyzed by pathology, it was observed that KEAP1 gene expression levels was higher in GM patients compared with controls (GM:0,2059; CTL: 0,09717; p=0,009). No association was observed between MDS and CTL; however RCDM patients have lower levels of NFE2L2 (RCMD: 1,754; CTL: 5,033; p<0,05) and higher levels of KEAP1 (RCMD: 0,185; CTL: 0,097; p=0,005). Furthermore, our preliminary results for NQO1 gene expression showed that MDS patients present lower levels than controls (MDS: 0,1884; CTL: 01969; p=0,0058). No associations were found between clinical and laboratory data (erythropoietin and ferritin levels) and the analyzed genes. Through ROC analysis we observed that NFE2L2 (cut off <2,044; sensitivity: 75%; specificity: 83,3%) and KEAP1 levels (cut off >0,1627; sensitivity: 54,17%; specificity: 86,67%) might be diagnostic biomarkers for RCMD patients, as well as, NQO1 levels for MDS patients (cut off > 0,00654; sensitivity: 74,29%; specificity: 78,26%). Also, KEAP1 levels might be biomarkers for MM patients (cut off >0,1645; sensitivity: 52,38%; specificity: 86,67%). Survival analysis showed that RCMD patients with NFE2L2 expression levels over 2,044 and KEAP1 levels under 0,1645 present a tendency for lower survival. The same is observed in MM patients with KEAP1 levels under 0,1645.
Conclusion
Our results suggest that the expression pattern of NFE2L2, KEAP1 and NQO1 genes might be associated with the development of hematological malignancies, and may have a great potential as diagnostic and prognostic biomarkers for Myelodysplastic Syndrome and Multiple Myeloma.This study is supported by Center of Investigation in Environment Genetics and Oncobiology (CIMAGO), Jorge J. by LPCC-NRC/CIMAGO 2015 Grant, Pires A. by LPCC-Pfizer 2015 Grant andAlves R. is supported by Portuguese Foundation to Science (FCT) grant (SFRH/BD/51994/2012).
Session topic: E-poster
Keyword(s): Gene expression, MDS, Monoclonal gammopathy
Type: Publication Only
Background
Oxidative stress (OS) deregulation has been associated with almost all neoplastic diseases, including leukemia, where it contributes to disease development and progression. NRF2 (Nuclear factor erythroid-2-related factor 2) is a transcription factor codified by NFE2L2 gene (Nuclear factor erythroid2-like 2) that activate many antioxidant and detoxification genes, like the NQO1 (NAD(P)H:quinone oxidoreductase 1) gene, through its binding to antioxidant response element (ARE) and regulate ARE-mediated gene expression and induction. Moreover, NRF2 is strongly regulated by KEAP1 (Kelch-like ECH-associated protein 1). NRF2-KEAP1 system seems to have an extremely important role in OS regulation, contributing for disease development and/or influence therapy response.
Aims
Our aim was to evaluate the expression levels of NFE2L2, KEAP1 and NQO1 genes in Myelodysplastic Syndrome (MDS) and Monoclonal Gammopathies (MG) patients, and its correlation with clinical and laboratorial data, in order to identify potential biomarkers of diagnosis and/or prognosis.
Methods
We evaluated 135 samples, 53 MDS (26 refractory cytopenia with multilineage dysplasia; 8 chronic myelomonocytic leukemia; 7 refractory cytopenia with unilineage dysplasia; 5 refractory anemia with excess blasts-1; 4 refractory anemia with ringed sideroblasts; 2 refractory anemia with excess blasts-2; 1 5q-), 40 MG (15 monoclonal gammopathies of undetermined significance; 25 multiple myeloma) and 42 controls (Ctl). Samples were collected after informed consent obtained in accordance with the Helsinki Declaration. Real-time PCR was used to evaluate the gene expression level of NFE2L2, KEAP1, NQO1 andGUS (control gene). Results were considered statistically significant when p<0,05.
Results
Our results showed that patient´s group presents higher KEAP1 expression levels comparing to controls (Patients: 0,175; CTL: 0,097; p=0,04), while NFE2L2did not presented differences between any groups. When we analyzed by pathology, it was observed that KEAP1 gene expression levels was higher in GM patients compared with controls (GM:0,2059; CTL: 0,09717; p=0,009). No association was observed between MDS and CTL; however RCDM patients have lower levels of NFE2L2 (RCMD: 1,754; CTL: 5,033; p<0,05) and higher levels of KEAP1 (RCMD: 0,185; CTL: 0,097; p=0,005). Furthermore, our preliminary results for NQO1 gene expression showed that MDS patients present lower levels than controls (MDS: 0,1884; CTL: 01969; p=0,0058). No associations were found between clinical and laboratory data (erythropoietin and ferritin levels) and the analyzed genes. Through ROC analysis we observed that NFE2L2 (cut off <2,044; sensitivity: 75%; specificity: 83,3%) and KEAP1 levels (cut off >0,1627; sensitivity: 54,17%; specificity: 86,67%) might be diagnostic biomarkers for RCMD patients, as well as, NQO1 levels for MDS patients (cut off > 0,00654; sensitivity: 74,29%; specificity: 78,26%). Also, KEAP1 levels might be biomarkers for MM patients (cut off >0,1645; sensitivity: 52,38%; specificity: 86,67%). Survival analysis showed that RCMD patients with NFE2L2 expression levels over 2,044 and KEAP1 levels under 0,1645 present a tendency for lower survival. The same is observed in MM patients with KEAP1 levels under 0,1645.
Conclusion
Our results suggest that the expression pattern of NFE2L2, KEAP1 and NQO1 genes might be associated with the development of hematological malignancies, and may have a great potential as diagnostic and prognostic biomarkers for Myelodysplastic Syndrome and Multiple Myeloma.This study is supported by Center of Investigation in Environment Genetics and Oncobiology (CIMAGO), Jorge J. by LPCC-NRC/CIMAGO 2015 Grant, Pires A. by LPCC-Pfizer 2015 Grant andAlves R. is supported by Portuguese Foundation to Science (FCT) grant (SFRH/BD/51994/2012).
Session topic: E-poster
Keyword(s): Gene expression, MDS, Monoclonal gammopathy
Abstract: PB1923
Type: Publication Only
Background
Oxidative stress (OS) deregulation has been associated with almost all neoplastic diseases, including leukemia, where it contributes to disease development and progression. NRF2 (Nuclear factor erythroid-2-related factor 2) is a transcription factor codified by NFE2L2 gene (Nuclear factor erythroid2-like 2) that activate many antioxidant and detoxification genes, like the NQO1 (NAD(P)H:quinone oxidoreductase 1) gene, through its binding to antioxidant response element (ARE) and regulate ARE-mediated gene expression and induction. Moreover, NRF2 is strongly regulated by KEAP1 (Kelch-like ECH-associated protein 1). NRF2-KEAP1 system seems to have an extremely important role in OS regulation, contributing for disease development and/or influence therapy response.
Aims
Our aim was to evaluate the expression levels of NFE2L2, KEAP1 and NQO1 genes in Myelodysplastic Syndrome (MDS) and Monoclonal Gammopathies (MG) patients, and its correlation with clinical and laboratorial data, in order to identify potential biomarkers of diagnosis and/or prognosis.
Methods
We evaluated 135 samples, 53 MDS (26 refractory cytopenia with multilineage dysplasia; 8 chronic myelomonocytic leukemia; 7 refractory cytopenia with unilineage dysplasia; 5 refractory anemia with excess blasts-1; 4 refractory anemia with ringed sideroblasts; 2 refractory anemia with excess blasts-2; 1 5q-), 40 MG (15 monoclonal gammopathies of undetermined significance; 25 multiple myeloma) and 42 controls (Ctl). Samples were collected after informed consent obtained in accordance with the Helsinki Declaration. Real-time PCR was used to evaluate the gene expression level of NFE2L2, KEAP1, NQO1 andGUS (control gene). Results were considered statistically significant when p<0,05.
Results
Our results showed that patient´s group presents higher KEAP1 expression levels comparing to controls (Patients: 0,175; CTL: 0,097; p=0,04), while NFE2L2did not presented differences between any groups. When we analyzed by pathology, it was observed that KEAP1 gene expression levels was higher in GM patients compared with controls (GM:0,2059; CTL: 0,09717; p=0,009). No association was observed between MDS and CTL; however RCDM patients have lower levels of NFE2L2 (RCMD: 1,754; CTL: 5,033; p<0,05) and higher levels of KEAP1 (RCMD: 0,185; CTL: 0,097; p=0,005). Furthermore, our preliminary results for NQO1 gene expression showed that MDS patients present lower levels than controls (MDS: 0,1884; CTL: 01969; p=0,0058). No associations were found between clinical and laboratory data (erythropoietin and ferritin levels) and the analyzed genes. Through ROC analysis we observed that NFE2L2 (cut off <2,044; sensitivity: 75%; specificity: 83,3%) and KEAP1 levels (cut off >0,1627; sensitivity: 54,17%; specificity: 86,67%) might be diagnostic biomarkers for RCMD patients, as well as, NQO1 levels for MDS patients (cut off > 0,00654; sensitivity: 74,29%; specificity: 78,26%). Also, KEAP1 levels might be biomarkers for MM patients (cut off >0,1645; sensitivity: 52,38%; specificity: 86,67%). Survival analysis showed that RCMD patients with NFE2L2 expression levels over 2,044 and KEAP1 levels under 0,1645 present a tendency for lower survival. The same is observed in MM patients with KEAP1 levels under 0,1645.
Conclusion
Our results suggest that the expression pattern of NFE2L2, KEAP1 and NQO1 genes might be associated with the development of hematological malignancies, and may have a great potential as diagnostic and prognostic biomarkers for Myelodysplastic Syndrome and Multiple Myeloma.This study is supported by Center of Investigation in Environment Genetics and Oncobiology (CIMAGO), Jorge J. by LPCC-NRC/CIMAGO 2015 Grant, Pires A. by LPCC-Pfizer 2015 Grant andAlves R. is supported by Portuguese Foundation to Science (FCT) grant (SFRH/BD/51994/2012).
Session topic: E-poster
Keyword(s): Gene expression, MDS, Monoclonal gammopathy
Type: Publication Only
Background
Oxidative stress (OS) deregulation has been associated with almost all neoplastic diseases, including leukemia, where it contributes to disease development and progression. NRF2 (Nuclear factor erythroid-2-related factor 2) is a transcription factor codified by NFE2L2 gene (Nuclear factor erythroid2-like 2) that activate many antioxidant and detoxification genes, like the NQO1 (NAD(P)H:quinone oxidoreductase 1) gene, through its binding to antioxidant response element (ARE) and regulate ARE-mediated gene expression and induction. Moreover, NRF2 is strongly regulated by KEAP1 (Kelch-like ECH-associated protein 1). NRF2-KEAP1 system seems to have an extremely important role in OS regulation, contributing for disease development and/or influence therapy response.
Aims
Our aim was to evaluate the expression levels of NFE2L2, KEAP1 and NQO1 genes in Myelodysplastic Syndrome (MDS) and Monoclonal Gammopathies (MG) patients, and its correlation with clinical and laboratorial data, in order to identify potential biomarkers of diagnosis and/or prognosis.
Methods
We evaluated 135 samples, 53 MDS (26 refractory cytopenia with multilineage dysplasia; 8 chronic myelomonocytic leukemia; 7 refractory cytopenia with unilineage dysplasia; 5 refractory anemia with excess blasts-1; 4 refractory anemia with ringed sideroblasts; 2 refractory anemia with excess blasts-2; 1 5q-), 40 MG (15 monoclonal gammopathies of undetermined significance; 25 multiple myeloma) and 42 controls (Ctl). Samples were collected after informed consent obtained in accordance with the Helsinki Declaration. Real-time PCR was used to evaluate the gene expression level of NFE2L2, KEAP1, NQO1 andGUS (control gene). Results were considered statistically significant when p<0,05.
Results
Our results showed that patient´s group presents higher KEAP1 expression levels comparing to controls (Patients: 0,175; CTL: 0,097; p=0,04), while NFE2L2did not presented differences between any groups. When we analyzed by pathology, it was observed that KEAP1 gene expression levels was higher in GM patients compared with controls (GM:0,2059; CTL: 0,09717; p=0,009). No association was observed between MDS and CTL; however RCDM patients have lower levels of NFE2L2 (RCMD: 1,754; CTL: 5,033; p<0,05) and higher levels of KEAP1 (RCMD: 0,185; CTL: 0,097; p=0,005). Furthermore, our preliminary results for NQO1 gene expression showed that MDS patients present lower levels than controls (MDS: 0,1884; CTL: 01969; p=0,0058). No associations were found between clinical and laboratory data (erythropoietin and ferritin levels) and the analyzed genes. Through ROC analysis we observed that NFE2L2 (cut off <2,044; sensitivity: 75%; specificity: 83,3%) and KEAP1 levels (cut off >0,1627; sensitivity: 54,17%; specificity: 86,67%) might be diagnostic biomarkers for RCMD patients, as well as, NQO1 levels for MDS patients (cut off > 0,00654; sensitivity: 74,29%; specificity: 78,26%). Also, KEAP1 levels might be biomarkers for MM patients (cut off >0,1645; sensitivity: 52,38%; specificity: 86,67%). Survival analysis showed that RCMD patients with NFE2L2 expression levels over 2,044 and KEAP1 levels under 0,1645 present a tendency for lower survival. The same is observed in MM patients with KEAP1 levels under 0,1645.
Conclusion
Our results suggest that the expression pattern of NFE2L2, KEAP1 and NQO1 genes might be associated with the development of hematological malignancies, and may have a great potential as diagnostic and prognostic biomarkers for Myelodysplastic Syndrome and Multiple Myeloma.This study is supported by Center of Investigation in Environment Genetics and Oncobiology (CIMAGO), Jorge J. by LPCC-NRC/CIMAGO 2015 Grant, Pires A. by LPCC-Pfizer 2015 Grant andAlves R. is supported by Portuguese Foundation to Science (FCT) grant (SFRH/BD/51994/2012).
Session topic: E-poster
Keyword(s): Gene expression, MDS, Monoclonal gammopathy
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