Pharmacologic induction of PGC-1α stimulates fetal haemoglobin gene expression.

Autor: Sun Y; Department of Medicine, Section of Hematology-Medical Oncology, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA., Habara A; Department of Medicine, Section of Hematology-Medical Oncology, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA.; Department of Clinical Biochemistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia., Le CQ; Department of Medicine, Section of Hematology-Medical Oncology, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA., Nguyen N; Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, Massachusetts, USA., Chen R; Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, Massachusetts, USA., Murphy GJ; Department of Medicine, Section of Hematology-Medical Oncology, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA.; Center for Regenerative Medicine, Boston University, Boston Medical Center, Boston, Massachusetts, USA., Chui DHK; Department of Medicine, Section of Hematology-Medical Oncology, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA., Steinberg MH; Department of Medicine, Section of Hematology-Medical Oncology, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA., Cui S; Department of Medicine, Section of Hematology-Medical Oncology, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2022 Apr; Vol. 197 (1), pp. 97-109. Date of Electronic Publication: 2022 Feb 04.
DOI: 10.1111/bjh.18042
Abstrakt: Sickle cell disease (SCD) is a genetic disorder that affects millions around the world. Enhancement of fetal γ-globin levels and fetal haemoglobin (HbF) production in SCD patients leads to diminished severity of many clinical features of the disease. We recently identified the transcriptional co-activator PGC-1α as a new protein involved in the regulation of the globin genes. Here, we report that upregulation of PGC-1α by infection with a lentivirus expressing PGC-1α or by the small-molecule PGC-1α agonist ZLN005 in human primary erythroid progenitor CD34 + cells induces both fetal γ-globin mRNA and protein expression as well as the percentage of HbF-positive cell (F cells) without significantly affecting cell proliferation and differentiation. We further found that the combination of ZLN005 and hydroxyurea (hydroxycarbamide) exhibited an additive effect on the expression of γ-globin and the generation of F cells from cultured CD34 + cells. In addition, ZLN005 induced robust expression of the murine embryonic βh1-globin gene and to a lesser extent, human γ-globin gene expression in sickle mice. These findings suggest that activation of PGC-1α by ZLN005 might provide a new path for modulating HbF levels with potential therapeutic benefit in β-hemoglobinopathies.
(© 2022 British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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