Identification of novel γ-globin inducers among all potential erythroid druggable targets
Issued Date
2022-06-14
Resource Type
ISSN
24739529
eISSN
24739537
Scopus ID
2-s2.0-85132350800
Pubmed ID
35240686
Journal Title
Blood Advances
Volume
6
Issue
11
Start Page
3280
End Page
3285
Rights Holder(s)
SCOPUS
Bibliographic Citation
Blood Advances Vol.6 No.11 (2022) , 3280-3285
Suggested Citation
Yu L., Myers G., Schneider E., Wang Y., Mathews R., Lim K.C., Siemieniak D., Tang V., Ginsburg D., Balbin-Cuesta G., Singh S.A., Phuwakanjana P., Jearawiriyapaisarn N., Khoriaty R., Engel J.D. Identification of novel γ-globin inducers among all potential erythroid druggable targets. Blood Advances Vol.6 No.11 (2022) , 3280-3285. 3285. doi:10.1182/bloodadvances.2021006802 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/85794
Title
Identification of novel γ-globin inducers among all potential erythroid druggable targets
Other Contributor(s)
Abstract
Human γ-globin is predominantly expressed in fetal liver erythroid cells during gestation from 2 nearly identical genes, HBG1 and HBG2, that are both perinatally silenced. Reactivation of these fetal genes in adult red blood cells can ameliorate many symptoms associated with the inherited β-globinopathies, sickle cell disease, and Cooley anemia. Although promising genetic strategies to reactivate the g-globin genes to treat these diseases have been explored, there are significant barriers to their effective implementation worldwide; alternatively, pharmacological induction of γ-globin synthesis could readily reach the majority of affected individuals. In this study, we generated a CRISPR knockout library that targeted all erythroid genes for which prospective or actual therapeutic compounds already exist. By probing this library for genes that repress fetal hemoglobin (HbF),we identified several novel, potentially druggable, γ-globin repressors, including VHL and PTEN. We demonstrate that deletion of VHL induces HbF through activation of the HIF1α pathway and that deletion of PTEN induces HbF through AKT pathway stimulation. Finally, we show that small-molecule inhibitors of PTEN and EZH induce HbF in both healthy and β-thalassemic human primary erythroid cells.