A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease.
OBJECTIVE
To report on molecular mechanisms of fetal hemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of sickle cell disease.


METHODS
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.
a 1 Department of Medicine, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, Republic of South Africa.
Gift D
GD
Pule
Shaheen
S
Mowla
Nicolas
N
Novitzky
Charles S
CS
Wiysonge
Ambroise
A
Wonkam
D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000986:Antisickling Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D044127:Epigenesis, Genetic; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology / Q000627:therapeutic use*; D035683:MicroRNAs / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction / Q000187:drug effects; D055545:gamma-Globins / Q000235:genetics / Q000378:metabolism
D000986:Antisickling Agents; D035683:MicroRNAs; D055545:gamma-Globins; D005319:Fetal Hemoglobin; D000242:Cyclic AMP; D006152:Cyclic GMP; D006918:Hydroxyurea
BCL11A; HBS1L-MYB and SAR1; fetal hemoglobin; hydroxyurea; molecular mechanism; sickle cell disease