UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells.
Tiwaporn NualkaewPinyaphat KhamphikhamPhitchapa PongpaksupasinWoratree KaewsakulthongDuantida SongdejKittiphong PaiboonsukwongOrapan SripichaiJames Douglas EngelSuradej HongengSuthat FucharoenNatee JearawiriyapaisarnPublished in: Annals of hematology (2020)
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.
Keyphrases
- poor prognosis
- dna methylation
- end stage renal disease
- small molecule
- ejection fraction
- newly diagnosed
- acute myeloid leukemia
- binding protein
- peritoneal dialysis
- genome wide
- gene expression
- endothelial cells
- sickle cell disease
- prognostic factors
- induced apoptosis
- emergency department
- transcription factor
- drug delivery
- signaling pathway
- cell death
- endoplasmic reticulum stress
- cell cycle arrest
- combination therapy
- induced pluripotent stem cells
- adverse drug
- genome wide identification