A study based on genetic data from over 28 thousand individuals revealed a potential mechanism for developing new treatments for hereditary blood diseases, such as sickle cell anemia and beta-thalassemia.
The research, published in the scientific journal Nature and involving Brazilian researchers from the Faculty of Medicine of the University of São Paulo (FMUSP), focused on the role of the BACH2 protein in modulating fetal hemoglobin, the predominant form of hemoglobin during gestation.
Scientists discovered that this protein acts as an inhibitor of fetal hemoglobin production. By decreasing this inhibitory function in cells cultured in the laboratory, it was possible to increase the amount of fetal hemoglobin produced.
Ester Sabino, immunologist and head of the Department of Pathology at the USP Faculty of Medicine, emphasizes that it was already known that individuals with high levels of fetal hemoglobin during intrauterine life tend to show improvements in sickle cell anemia.
This discovery expands the understanding of the processes that control the production of this protein and points to a viable path for creating new therapeutic approaches. Sabino comments that every advance in understanding protein production facilitates the search for treatment methods for patients.
Functioning of the Identified Mechanism
Hemoglobin, a protein found in red blood cells, is essential for transporting oxygen throughout the body. During human development, it gradually transitions from the fetal form to the dominant adult form.
In cases of sickle cell anemia, a genetic mutation causes abnormal functioning of adult hemoglobin, resulting in the deformation of red blood cells. In beta-thalassemia, the hereditary condition is marked by insufficient or absent production of one of the components of adult hemoglobin.
In these scenarios, increasing the production of fetal hemoglobin is considered a strategy of clinical interest. The study investigated the regulatory genetic mechanisms of this production and identified BACH2 as a limiting factor.
The research group observed that a genetic variation linked to higher levels of fetal hemoglobin leads to decreased expression of BACH2. Laboratory experiments confirmed that reducing or inhibiting this protein also increased fetal hemoglobin expression. Furthermore, the results showed that BACH2 limits activation promoted by NRF2, establishing a regulatory mechanism available for future exploration.
To investigate the genetic factors related to fetal hemoglobin production, researchers analyzed data from 28,279 people from diverse backgrounds. The analysis identified 91 distinct genetic associations spread across 12 regions of the genome. In one of these areas, a variant was found associated with both higher levels of fetal hemoglobin and lower expression of BACH2.
Sabino emphasizes the importance of a large volume of participants from different locations in genetic studies to achieve significant discoveries. Based on this genetic clue, the team conducted tests to verify the direct role of the protein in regulating fetal hemoglobin, validating the relationship seen in the genetic analysis and elucidating the biological process involved.
The combination of population genetic data with functional experiments was crucial in connecting the identified variant to the action of BACH2 in fetal hemoglobin production.
Combination of Strategies Shows Promising Result
The study also examined the interaction between BACH2 and BCL11A, another known regulator of fetal hemoglobin production and a target for therapies. Tests demonstrated that both proteins operate through independent pathways. When the action of BACH2 and BCL11A was reduced jointly, there was an increase in fetal hemoglobin greater than that obtained by reducing each protein separately.
This finding suggests that intervening in multiple regulatory mechanisms could be a promising route for research aimed at increasing fetal hemoglobin. However, despite the potential, the discovery still requires more steps before being considered a treatment option. The researchers warn that current experiments do not prove the safety or efficacy of the strategy in patients.
Ester Sabino concludes that this is only the beginning; after understanding the mechanisms, it is imperative to initially test in animal models and subsequently conduct studies in humans to then develop a safe treatment.


