The clinical severity of the beta thalassemia syndromes and hemoglobinopathies can be dramatically modified by up-regulation of basal fetal globin expression through co-inheritance of 3 influential genetic modifiers, or by fetal globin-inducing therapeutics. One approved therapeutic, Hydroxyurea (HU), benefits some patients, but does not reduce anemia enough to achieve transfusion-independence in many thalassemia patients, and additional HbF-enhancing therapies are needed which can be applied in combination regimens without added toxicity. A challenge to successful application of HbF-inducing therapies is the broad genetic heterogeneity, which produces variable baseline HbF levels, and, to date, unpredictable responsiveness to therapeutics among individual patients. Therapies tailored to genetic modifiers (QTL) which modulate baseline HbF levels would allow rational treatment selection for specific subsets of patients. GWAS screening of 1000 patients in diverse populations, and analyses of patients enrolled on two recent clinical trials in sickle cell disease and beta thalassemia, demonstrated that modifiers in the 3 most influential QTLs which increase HbF or F-cells occur commonly, in 30–50% of patients, with BCL11A polymorphisms occurring in 20–30%. Using molecular modeling and high-throughput screening of chemical libraries, we recently discovered 8 therapeutics (6 clinical-stage or approved) which enhance HbF expression through different mechanisms, including displacement of a repressor complex containing HDAC-3 (RB7) or suppression of BCL11A mRNA (MS-275). Two pan-HDAC inhibitors (Butyrate and MS-275) profoundly decrease the 3 BCL11A isoforms by 80–100% in normal erythroid progenitors, while other HDAC inhibitors (LBH389, SAHA) have no effect or even increase BCL11A expression. Decreases in BCL11A provide a favorable effect, similar to the BCL11A QTL, increasing both baseline HbF levels and responsiveness to HbF-inducing drugs. Other inducers (DLT, Benserazide, NSC95397, RB16, ST20) induce the gamma-globin promoter without epigenetic effects. MS-275, DLT, and RB7 increase the promoter activity by 5–6 fold in normal progenitors, while prior generation short chain fatty acid agents induced by 2-fold. This small but diverse therapeutic pipeline, encompassing different mechanisms of action, now allows: 1) epigenetic and/or non-epigenetic gamma-globin induction; 2) significantly higher induction than prior generation inducers; and 3) potential drug combinations which may benefit those patients who do not have favorable QTL polymorphisms. Individual therapeutics can now be investigated in genotyped subjects to provide a basis for tailoring specific inducer combinations to QTL profiles, offering potential for higher therapeutic benefit.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.