UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells

Abstract

Increased expression of fetal hemoglobin (HbF) improves the clinical severity of β-thalassemia patients. EHMT1/2 histone methyltransferases are epigenetic modifying enzymes that are responsible for catalyzing addition of the repressive histone mark H3K9me2 at silenced genes, including the γ-globin genes. UNC0638, a chemical inhibitor of EHMT1/2, has been shown to induce HbF expression in human erythroid progenitor cell cultures. Here, we report the HbF-inducing activity of UNC0638 in erythroid progenitor cells from β-thalassemia/HbE patients. UNC0638 treatment led to significant increases in γ-globin mRNA, HbF expression, and HbF-containing cells in the absence of significant cytotoxicity. Moreover, UNC0638 showed additive effects on HbF induction in combination with the immunomodulatory drug pomalidomide and the DNMT1 inhibitor decitabine. These studies provide a scientific proof of concept that a small molecule targeting EHMT1/2 epigenetic enzymes, used alone or in combination with pomalidomide or decitabine, is a potential therapeutic approach for HbF induction. Further development of structural analogs of UNC0638 with similar biological effects but improved pharmacokinetic properties may lead to promising therapies and possible clinical application for the treatment of β-thalassemia.

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Acknowledgments

The authors would like to thank the patients and their families for their contributions to this study, and Thongperm Munkongdee, Nattrika Buasuwan, and Nurmeeha Hinna for their assistance with the DNA diagnosis for thalassemia and hemoglobin analysis. The technical assistance of Greggory Myers and the editorial assistance of Kim-Chew Lim (all at the University of Michigan) is greatly appreciated.

Funding

This work was supported by grants from Mahidol University; the Thailand Research Fund (MRG5680092); the Office of the Higher Education Commission; and the Program Management Unit for Human resources & Institutional Development, Research and Innovation to N.J. P.P was supported by the Siriraj Graduate Scholarship.

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Contribution: T.N., P.K., and N.J. designed the research; T.N., P.K., P.P., and W.K. performed the experiments; T.N., P.K., and N.J. analyzed the data; D.S., K.P., S.H., and S.F. provided the samples and resources; T.N., J.D.E., and N.J. wrote the manuscript; O.S., J.D.E., S.H., S.F., and N.J. conceptualized the idea and supervised the project; and all the authors read and approved the final manuscript.

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Correspondence to Natee Jearawiriyapaisarn.

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The study was approved by Institutional Review Boards of Mahidol University and was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all participants before being included in the study.

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Nualkaew, T., Khamphikham, P., Pongpaksupasin, P. et al. UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells. Ann Hematol (2020). https://doi.org/10.1007/s00277-020-04136-w

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Keywords

  • Fetal hemoglobin induction
  • β-Thalassemia/HbE
  • UNC0638
  • Pomalidomide
  • Decitabine