AIM: To report on molecular mechanisms of fetal hemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of sickle cell disease. STUDY DESIGN: Systematic review. RESULTS: Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways that modulate γ-globin expression (cAMP/cGMP; Giα/c-Jun N-terminal kinase/Jun; methylation and miRNA). Three main molecular pathways have been reported: i) Epigenetic modifications, transcriptional events and signaling pathways involved in HU-mediated response, ii) Signaling pathways involving HU-mediated response and iii) Post-transcriptional pathways (regulation by miRNAs). CONCLUSIONS: The complete picture of HU-mediated mechanisms of HbF production in Sickle Cell Disease remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome.
AIM: To report on molecular mechanisms of fetal hemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of sickle cell disease. STUDY DESIGN: Systematic review. RESULTS: Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways that modulate γ-globin expression (cAMP/cGMP; Giα/c-Jun N-terminal kinase/Jun; methylation and miRNA). Three main molecular pathways have been reported: i) Epigenetic modifications, transcriptional events and signaling pathways involved in HU-mediated response, ii) Signaling pathways involving HU-mediated response and iii) Post-transcriptional pathways (regulation by miRNAs). CONCLUSIONS: The complete picture of HU-mediated mechanisms of HbF production in Sickle Cell Disease remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome.
Authors: Jane S Hankins; Russell E Ware; Zora R Rogers; Lynn W Wynn; Peter A Lane; J Paul Scott; Winfred C Wang Journal: Blood Date: 2005-10-01 Impact factor: 22.113
Authors: Vivien A Sheehan; Zhaoyu Luo; Jonathan M Flanagan; Thad A Howard; Bruce W Thompson; Winfred C Wang; Abdullah Kutlar; Russell E Ware Journal: Am J Hematol Date: 2013-05-30 Impact factor: 10.047
Authors: Gabriela Queila de Carvalho-Siqueira; Galina Ananina; Bruno Batista de Souza; Murilo Guimarães Borges; Mirta Tomie Ito; Sueli Matilde da Silva-Costa; Igor de Farias Domingos; Diego Arruda Falcão; Iscia Lopes-Cendes; Marcos André Cavalcanti Bezerra; Aderson da Silva Araújo; Antônio Roberto Lucena-Araújo; Marilda de Souza Gonçalves; Sara Teresinha Olalla Saad; Fernando Ferreira Costa; Mônica Barbosa de Melo Journal: Exp Biol Med (Maywood) Date: 2019-05-12