Hydroxyurea-Induced miRNA Expression in Sickle Cell Disease Patients in Africa.

Khuthala Mnika,Emile R Chimusa,Gift D Pule,Neil A Hanchard,Mario Jonas,Gaston K Mazandu,Ambroise Wonkam

doi:10.3389/fgene.2019.00509

Abstract

Hydroxyurea (HU) is clinically beneficial in sickle cell disease (SCD) through fetal hemoglobin (HbF) induction; however, the mechanism of HU is not yet fully elucidated. Selected miRNAs have been associated with HU-induced HbF production. We have investigated differential HU-induced global miRNA expression in peripheral blood of adult SCD patients in patients from Congo, living in South Africa. We found 22 of 798 miRNAs evaluated that were differentially expressed under HU treatment, with the majority (13/22) being functionally associated with HbF-regulatory genes, including BCL11A (miR-148b-3p, miR-32-5p, miR-340-5p, and miR-29c-3p), MYB (miR-105-5p), and KLF-3 (miR-106b-5), and SP1 (miR-29b-3p, miR-625-5p, miR-324-5p, miR-125a-5p, miR-99b-5p, miR-374b-5p, and miR-145-5p). The preliminary study provides potential additional miRNA candidates for therapeutic exploration.

Highlights

Hydroxyurea (HU), the only food and drug administration (FDA) – approved treatment for sickle cell disease (SCD), is beneficial primarily through its ability to induce fetal hemoglobin (HbF) (Platt et al, 1984; Charache et al, 1992; Zimmerman et al, 2004)
Because recent studies have identified miRNAs in mature erythrocytes that may reflect miRNA regulated processes during early erythropoiesis (Walker et al, 2011), we investigated differential HU-induced miRNA expressions using peripheral blood isolated from SCA patients before starting HU and after reaching the maximum tolerated dose (MTD)
Most patients had at least a Bantu haplotype, in the beta-globin genes’ cluster; four patients were heterozygous for the 3.7 kb alpha-globin gene deletion; detailed clinical characteristics are shown in Supplementary Table S1

Summary

Introduction

Hydroxyurea (HU), the only food and drug administration (FDA) – approved treatment for sickle cell disease (SCD), is beneficial primarily through its ability to induce fetal hemoglobin (HbF) (Platt et al, 1984; Charache et al, 1992; Zimmerman et al, 2004). Clinical trials have shown hydroxyurea to be efficacious for increasing HbF in children, adolescents, and adults with SCA (Charache et al, 1992; Lee and Ambros, 2001; Thornburg et al, 2009). Three main molecular pathways have been reported in HU-mediated response in increase HbF: (i) Epigenetic modifications, and transcriptional events, (ii) Signaling pathways, and (iii) Post-transcriptional pathways with regulation by Small non-coding RNA oligonucleotides (miRNA) (Pule et al, 2015). A few studies have demonstrated post-transcriptional regulation of HU-mediated γ-globin expression through miRNA in SCD patients; for example, miR-15a and miR-16-1 have been linked via the transcription factor MYB3 to elevated HbF

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Conclusion