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Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness

Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do n...

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Autores principales: Zhu, Xingguo, Hu, Tianxiang, Ho, Meng Hsuan, Wang, Yongchao, Yu, Miao, Patel, Niren, Pi, Wenhu, Choi, Jeong-Hyeon, Xu, Hongyan, Ganapathy, Vadivel, Kutlar, Ferdane, Kutlar, Abdullah, Tuan, Dorothy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709098/
https://www.ncbi.nlm.nih.gov/pubmed/28971909
http://dx.doi.org/10.3324/haematol.2017.175646
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author Zhu, Xingguo
Hu, Tianxiang
Ho, Meng Hsuan
Wang, Yongchao
Yu, Miao
Patel, Niren
Pi, Wenhu
Choi, Jeong-Hyeon
Xu, Hongyan
Ganapathy, Vadivel
Kutlar, Ferdane
Kutlar, Abdullah
Tuan, Dorothy
author_facet Zhu, Xingguo
Hu, Tianxiang
Ho, Meng Hsuan
Wang, Yongchao
Yu, Miao
Patel, Niren
Pi, Wenhu
Choi, Jeong-Hyeon
Xu, Hongyan
Ganapathy, Vadivel
Kutlar, Ferdane
Kutlar, Abdullah
Tuan, Dorothy
author_sort Zhu, Xingguo
collection PubMed
description Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured from peripheral blood CD34(+) cells of patients with SCD, we found that HU-induced changes in the protein but not the RNA levels of activator GATA-2 and repressors GATA-1, BCL11A and TR4 correlated with HU-induced changes in fetal hemoglobin (HbF) levels in the peripheral blood of HU high and low responders. However, HU did not significantly induce changes in the protein or RNA levels of activators NF-Y and NF-E4. Based on HU-induced changes in the protein levels of GATA-2, -1 and BCL11A, we calculated an Index of Hydroxyurea Responsiveness (IndexHU-3). Compared to the HU-induced fold changes in the individual transcription factor protein levels, the numerical values of IndexHU-3 statistically correlated best with the HU-induced peripheral blood HbF levels of the patients. Thus, IndexHU-3 can serve as an appropriate indicator for inherent HU responsiveness of patients with SCD.
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spelling pubmed-57090982017-12-12 Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness Zhu, Xingguo Hu, Tianxiang Ho, Meng Hsuan Wang, Yongchao Yu, Miao Patel, Niren Pi, Wenhu Choi, Jeong-Hyeon Xu, Hongyan Ganapathy, Vadivel Kutlar, Ferdane Kutlar, Abdullah Tuan, Dorothy Haematologica Article Hydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured from peripheral blood CD34(+) cells of patients with SCD, we found that HU-induced changes in the protein but not the RNA levels of activator GATA-2 and repressors GATA-1, BCL11A and TR4 correlated with HU-induced changes in fetal hemoglobin (HbF) levels in the peripheral blood of HU high and low responders. However, HU did not significantly induce changes in the protein or RNA levels of activators NF-Y and NF-E4. Based on HU-induced changes in the protein levels of GATA-2, -1 and BCL11A, we calculated an Index of Hydroxyurea Responsiveness (IndexHU-3). Compared to the HU-induced fold changes in the individual transcription factor protein levels, the numerical values of IndexHU-3 statistically correlated best with the HU-induced peripheral blood HbF levels of the patients. Thus, IndexHU-3 can serve as an appropriate indicator for inherent HU responsiveness of patients with SCD. Ferrata Storti Foundation 2017-12 /pmc/articles/PMC5709098/ /pubmed/28971909 http://dx.doi.org/10.3324/haematol.2017.175646 Text en Copyright© 2017 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
spellingShingle Article
Zhu, Xingguo
Hu, Tianxiang
Ho, Meng Hsuan
Wang, Yongchao
Yu, Miao
Patel, Niren
Pi, Wenhu
Choi, Jeong-Hyeon
Xu, Hongyan
Ganapathy, Vadivel
Kutlar, Ferdane
Kutlar, Abdullah
Tuan, Dorothy
Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness
title Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness
title_full Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness
title_fullStr Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness
title_full_unstemmed Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness
title_short Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness
title_sort hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with index of hydroxyurea responsiveness
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709098/
https://www.ncbi.nlm.nih.gov/pubmed/28971909
http://dx.doi.org/10.3324/haematol.2017.175646
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