Posted December 30, 2014
Bing Su, Ph.D., Yale University
The human immune system is able to respond specifically to millions of different foreign antigens by rearranging the sequence of genes that code for antigen receptors to create new receptors to the foreign challenge. Proteins called recombination activating genes-1 and -2 (RAG1 and RAG2) chop up the antigen receptor genes and rearrange the pieces to make new antigen receptor genes. These proteins are active in B lymphocytes, commonly called B cells, only when immune receptor formation is occurring, and are regulated by a multi-protein complex called mTORC2. Out-of-control RAG activity is thought to be responsible for chromosomal rearrangements observed in some leukemias.
With support from an FY09 PRMRP Investigator-Initiated Research Award, Dr. Bing Su at Yale University set out to study the means by which mTORC2 regulates RAG activity. Dr. Su found that Sin1 in the mTORC2 complex specifically controls RAG activity through activation of Akt2 and FoxO1. Furthermore, Sin1 is required for B cell development and T cell differentiation and is involved in the regulation of several other cell functions. Repression of IL-1 by Sin1 in the mTORC2 complex is important for B cell differentiation and Sin1 in mTORC2 was found to regulate B cell growth and proliferation via upregulation of c-Myc. These findings suggested that mTORC2 inhibition might be a therapeutic target in leukemia and B cell tumors since elevated Akt and c-Myc are often associated with these conditions. In experiments in cell culture, Dr. Su and his team found that blockage of mTORC2 inhibited leukemia cell growth but did not induce cell death. They subsequently found that mTORC2 also plays an important role in protecting B cells against stress and nutrient deprivation in a mechanism involving the heat shock protein HSP90. Simultaneous inhibition of HSP90 and mTORC2 resulted in cell death in cultures and a strong anti-leukemic effect in leukemia-prone mice.
Dr. Su's findings indicate that Sin1 and the mTORC2 complex are involved in a variety of functions in B cells, and mTORC2 may be a fruitful target for anti-leukemic strategies, especially in combination with other approaches, such as HSP90 inhibition.
Liu P, Gan W, Inuzuka H, et al. 2013. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol 15(11):1340-1350.
Zhang F, Lazorchak AS, Liu D, et al. 2012. Inhibition of the mTORC2 and chaperone pathways to treat leukemia. Blood 119(25):6080-6088.
Lazorchak AS, Liu D, Facchinetti V, et al. 2010. Sin1-mTORC2 suppresses rag and il7r gene expression through Akt2 in B cells. Mol Cell 39(3):433-443.