2. Academic Validation
  3. UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells

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

  • Ann Hematol. 2020 Sep;99(9):2027-2036. doi: 10.1007/s00277-020-04136-w.
Tiwaporn Nualkaew 1,  Pinyaphat Khamphikham 1 2,  Phitchapa Pongpaksupasin 1 3,  Woratree Kaewsakulthong 1 3,  Duantida Songdej 4,  Kittiphong Paiboonsukwong 1,  Orapan Sripichai 5,  James Douglas Engel 6,  Suradej Hongeng 4,  Suthat Fucharoen 1,  Natee Jearawiriyapaisarn 7
Affiliations

Affiliations

  • 1 Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, 25/25 Phuttamonthon 4 Road, Salaya, Nakhon Pathom, 73170, Thailand.
  • 2 Department of Forensic Science, Faculty of Allied Health Sciences, Thammasat University, Pathum Thani, Thailand.
  • 3 Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
  • 4 Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
  • 5 National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand.
  • 6 Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
  • 7 Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, 25/25 Phuttamonthon 4 Road, Salaya, Nakhon Pathom, 73170, Thailand. natee.jea@mahidol.edu.
PMID: 32567028 DOI: 10.1007/s00277-020-04136-w
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.

Keywords

Decitabine; Fetal hemoglobin induction; Pomalidomide; UNC0638; β-Thalassemia/HbE.

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