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Identification of Two New Synthetic Histone Deacetylase Inhibitors That Modulate Globin Gene Expression in Erythroid Cells from Healthy Donors and Patients with Thalassemia

Istituto Pasteur–Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma "La Sapienza", Roma, Italy (A.M., D.R., S.V.); Dipartimento di Biologia Cellulare e Neuroscienze (K.J., A.D.N., E.A., G.M.) e Dipartimento di Ematologia, Oncologia e Medicina Molecolare (A.R.M.), Istituto Superiore di Sanità, Roma, Italy; Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Siena, Italy (S.M.); Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, Napoli, Italy (L.A., A.N.); Dipartimento di Scienze Biomediche e Biotecnologie, Università degli Studi di Cagliari, Cagliari, Italy (R.G.); Division of Molecular Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria (G.B.); and Department of Medicine and Myeloproliferative Disorders Research Consortium (MPD-RC), University of Illinois at Chicago, Chicago, Illinois (A.R.M.)

We have identified two new histone deacetylase (HDAC) inhibitors (9 and 24) capable of inducing the expression of -globin and/or -globin promoter-driven reporter genes in a synthetic model of Hb switch. Both compounds also increased, with different mechanisms, the /(+) ratio expressed in vitro by normal human erythroblasts. Compound 9 increased the levels of -globin mRNA and the /(+) ratio (both by 2-fold). Compound 24 increased by 3-fold the level of -globin and decreased by 2-fold that of -globin mRNA, increasing the /(+) ratio by 6-fold, and raising (by 50%) the cell HbF content. Both compounds raised the acetylation state of histone H4 in primary cells, an indication that their activity was mediated through HDAC inhibition. Compounds 9 and 24 were also tested as /(+) mRNA inducers in erythroblasts obtained from patients with ⁰ thalassemia. Progenitor cells from patients with ⁰ thalassemia generated in vitro morphologically normal proerythroblasts that, unlike normal cells, failed to mature in the presence of EPO and expressed low -globin levels but 10 times higher-than-normal levels of the hemoglobin-stabilizing protein (AHSP) mRNA. Both compounds ameliorated the impaired in vitro maturation in ⁰ thalassemic erythroblasts, decreasing AHSP expression to normal levels. In the case of two patients (of five analyzed), the improved erythroblast maturation was associated with detectable increases in the /(+) mRNA ratio. The low toxicity exerted by compounds 9 and 24 in all of the assays investigated suggests that these new HDAC inhibitors should be considered for personalized therapy of selected patients with ⁰ thalassemia.

Address correspondence to: Anna Rita Migliaccio, Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, viale Regina Elena 299, 00161 Roma, Italy. E-mail: migliar{at}iss.it