Open Access

Hasiru Ratnayake

• mTOR inhibitor rapamycin has been observed to induce fetal hemoglobin in patients of β-hemoglobinopathies, a group of disorders in which mutations in the gene responsible β-globin chains results in reduced or malformed RBC production, leading to anemia. The induction of fetal hemoglobin bypasses these mutations, as they are found on the gene responsible for adult hemoglobin. Following birth, the fetal hemoglobin gene is silenced, and the adult gene is activated through a process known as the hemoglobin switch. Rapamycin treatment reverses this hemoglobin switch but the mechanism by which it does so is currently unknown. Rapamycin functions through its inhibition of mTORC1, a protein complex responsible for nutrient- and growth factor-dependent cell growth and proliferation. This literature review seeks to collate existing information on the mTORC1 signalling pathway and the hemoglobin switch, allowing for a specific mechanism by which rapamycin induces fetal hemoglobin through its inhibition of mTORC1 to be hypothesized. Following the literature search, 55 studies on the mTORC1 pathway and 31 studies on the hemoglobin switch were summarized. Using the information gained from this, three hypotheses were put forward for the possible induction mechanism, out of which the primary hypothesis is based on the hemoglobin switching factor KLF1. This was based on the observation that the knockdown of Raptor, a crucial component of mTORC1, in mice caused a decreased expression of KLF1. As KLF1 is an essential component of the hemoglobin switch, this provides a direct link between the inhibition of mTORC1 and the reversal of the hemoglobin switch. Additionally, the efficiency of rapamycin in comparison to other methods of fetal hemoglobin was discussed, including newer generations of mTOR inhibitors developed using rapamycin as a foundation. Finally, possible avenues of research to confirm the validity of the proposed hypotheses and to address points of ignorance within each topic were discussed.