Hydroxyurea Decouples Persistent F-Cell Elevation and Induction of γ-Globin

Walker, Aisha L.; Crosby, Danielle; Miller, Valerie; Weidert, Frances; Ofori-Acquah, Solomon Fiifi

doi:10.1016/j.exphem.2022.07.005

Cited by 1 publication

(2 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Murine HBB genes in the Townes model were replaced by human HBG1 and HBBS genes and some proximal but not some distal gene-regulatory elements. The HbSS Townes humanized knock-in mouse model recapitulates human globin gene switching ( 35 ). HU suppresses erythropoiesis in Townes HbSS mice to create an early persistent F-cell phenotype without re-activating γ-globin transcription ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…The HbSS Townes humanized knock-in mouse model recapitulates human globin gene switching ( 35 ). HU suppresses erythropoiesis in Townes HbSS mice to create an early persistent F-cell phenotype without re-activating γ-globin transcription ( 35 ). Townes mouse HSCs, in contrast to human HSCs, fail to induce HbF to therapeutic levels after genetic disruption of the BCL11A binding site in the HBG1 promoter ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease

et al. 2023

View full text Add to dashboard Cite

In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor of BACH1. We investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology. In HepG2 liver cells, ASP8731 increased HMOX1 and FTH1 mRNA. In pulmonary endothelial cells, ASP8731 decreased VCAM1 mRNA in response to TNF-α and blocked a decrease in glutathione in response to hemin. Townes-SS mice were gavaged once per day for 4 weeks with ASP8731, hydroxyurea (HU) or vehicle. Both ASP8731 and HU inhibited heme-mediated microvascular stasis and in combination, ASP8731 significantly reduced microvascular stasis compared to HU alone. In Townes-SS mice, ASP8731 and HU markedly increased heme oxygenase-1 and decreased hepatic ICAM-1, NF-kB phospho-p65 protein expression in the liver, and white blood cell counts. In addition, ASP8731 increased gamma-globin expression and HbF+ cells (F-cells) as compared to vehicle-treated mice. In human erythroid differentiated CD34+ cells, ASP8731 increased HGB mRNA and increased the percentage of F-cells 2-fold in manner similar to HU. ASP8731 and HU when given together induced more HbF+ cells compared to either drug alone. In CD34+ cells from one donor that was non-responsive to HU, ASP8731 induced HbF+ cells ~2-fold. ASP8731 and HU also increased HBG and HBA, but not HBB mRNA in erythroid differentiated CD34+ cells derived from SCD patients. These data indicate that BACH1 may offer a new therapeutic target to treat SCD.

show abstract

Section: Discussionmentioning

confidence: 99%