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Meta-Analysis
. 2015 Oct;8(5):669-79.
doi: 10.1586/17474086.2015.1078235. Epub 2015 Sep 1.

A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease

Gift D Pule  1 , Shaheen Mowla, Nicolas Novitzky, Charles S Wiysonge, Ambroise Wonkam
Affiliations
Meta-Analysis

A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease

Gift D Pule et al. Expert Rev Hematol. 2015 Oct.

Abstract

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.

Keywords: BCL11A; HBS1L-MYB and SAR1; fetal hemoglobin; hydroxyurea; molecular mechanism; sickle cell disease.

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Conflict of interest statement

Competing interests disclosure

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Fig.1
Fig.1. Various HU-activated signal transduction pathways for γ-globin expression
Summarized pathways previously associated and/or induced by HU treatment in primary erythroid and K562 cells.
See this image and copyright information in PMC

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