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Expert Rev Hematol. 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.

Author information

1
a 1 Department of Medicine, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, Republic of South Africa.

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

PMID:
26327494
PMCID:
PMC4829639
DOI:
10.1586/17474086.2015.1078235
[Indexed for MEDLINE]
Free PMC Article

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