More than 100 years ago, sickle cell disease (SCD) became the first genetic disease for which a genetic mutation was cloned. Yet, to this day, no effective therapy exists. In 2011, researchers led by Dr. Stuart Orkin from Harvard Medical School made a critical breakthrough: They found that inactivating the Bcl11a (B cell CLL/lymphoma 11A) transcription factor rescues SCD phenotypes in sickle cell disease mouse models (Xu et al. 2011). The breakthrough provides proof of principle that BCL11A targeting is a potential therapy for human SCD and beta thalassemias.
During human development, the production of fetal hemoglobin (HbF) is silenced and replaced by the production of adult hemoglobin (HbA). One of the factors that mediate the HbF-to-HbA switch is BCL11A, a transcriptional repressor of HbF. Unfortunately, HbF silencing increases the severity of sickle cell disease and beta thalassemias. The Orkin team hypothesized that re-activating HbF production by targeting BCL11A could be an effective SCD therapy. They tested their hypothesis using various strains of genetically engineered laboratory mice. Here's what they found:
- Although Bcl11a-null mice die soon after birth, tissue-specific Bcl11a-deleted β-YAC mice – mice that harbor a human β-globin cluster transgene and in which Bcl11a is conditionally deleted by erythroid-specific Cre recombinase – have impaired HbF silencing and produce normal red blood cells.
- Within a week of administering interferon to β-YAC mice that harbor a floxed Bcl11a allele and an interferon-inducible Mx1-Cre allele*, HbF silencing is substantially relaxed.
- Deleting Bcl11a markedly enhances the ability of DNA demethylation and histone deacetylase (HDAC) inhibitors to re-activate HbF expression, suggesting that targeting these two factors along with Bcl11a would more effectively augment HbF production.
- An erythoid-specific, Cre-mediated, Bcl11a deletion completely corrects SCD phenotypes when introduced into either of two mouse SCD models available at The Jackson Laboratory – STOCK Hbatm1Paz Hbbtm1Tow Tg(HBA-HBBs)41Paz/J (003342) and B6;129-Hbatm1(HBA)Tow Hbbtm2(HBG1,HBB*)Tow/Hbbtm3(HBG1,HBB)Tow/J (013071). In these settings, HbF constitutes about 30% of the total hemoglobin and is distributed quite evenly among red blood cells.
In summary, the Orkin team demonstrated that Bcl11a is required to silence HbF production in adult sickle cell disease mouse models and is dispensable for producing normal, healthy red blood cells. Their findings suggested that inhibiting BCL11A and modulating epigenetic pathways – such as DNA demethylation and histone deacetylation – would be therapeutic to people with SCD or beta thalassemias.
*Note: These mice were produced by mating β-YAC mice that harbor a floxed Bcl11a allele to B6.Cg-Tg(Mx1-cre)1Cgn/J (003556) mice, which are available from The Jackson Laboratory's Cre Repository. The Repository provides the scientific community with a centralized, comprehensive set of well-characterized Cre Driver lines and related information resources.