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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. [ABSTRACT FROM AUTHOR]

Keywords: fetal haemoglobin induction; -thalassaemia/HbE; pomalidomide; hydroxyurea; decitabine EN fetal haemoglobin induction -thalassaemia/HbE pomalidomide hydroxyurea decitabine e240 e245 6 06/18/20 20200615 NES 200615 Studies have shown that increased expression of fetal haemoglobin (HbF; SB 2 sb SB 2 sb ) can ameliorate red blood cell deficiencies in patients with -thalassaemia and sickle cell disease (SCD).[[1], [3]] Pharmacological induction of HbF expression in -thalassaemia has been investigated using several classes of small molecules,[4] including 5-azacytidine,[5] decitabine,[6] hydroxyurea,[7] LSD1 inhibitors (tranylcypromine and RN-1),[[8]] and short chain fatty acid derivatives.[[10]] Among these molecules, hydroxyurea is the only U.S. Food and Drug Administration (FDA) currently approved drug for the treatment of SCD and/or -thalassaemia. SP 0 sp -thalassaemia/HbE precursors from patients of different SP 0 sp -thalassemic mutations (Table SI) showed similarly increased levels of HbF induction in response to pomalidomide treatment. GLO:1XW/15jun20:bjh16670-fig-0002.jpg PHOTO (COLOR): 2 Effect of pomalidomide and its combinations on erythroid differentiation and mRNA expression of HbF regulators in cultured erythroid cells from 0-thalassaemia/HbE patients. HbF-inducing effects of hydroxyurea (HU), decitabine (DAC), and RN-1 in erythroid cells from 0-thalassaemia/HbE patients. [Extracted from the article]