Context-dependent gene expression programs promote lymphocyte development and function and suppress transformation.

摘要

Coordinated orchestration of gene expression programs at the transcriptional, post-transcriptional, and post-translational levels is essential for development and function of all cells, including lymphocytes. Normal tissue function also demands that the genome be faithfully passed from mother to daughter cell during the many rounds of cell division required to generate a mammalian organism. Genome integrity is maintained in part by integration of DNA damage signaling with cell cycle control. These mechanisms are especially critical for lymphocytes following V(D)J recombination, since V(D)J recombination involves genetic cutting and pasting of germline gene segments to form antigen receptors (AgRs). Using conditional deletion of the p53 tumor suppressor in mice, I found that p53 promotes genome stability in developmental stage-specific ways. Inactivation of p53 beginning in hematopoietic stem cells yields thymic tumors with aneuploidy; whereas deletion of p53 at the beginning of thymocyte development results in tumors bearing T cell AgR translocations. I also show that downregulation of the G1 phase cyclin D3 occurs in immature B and T cells in response to exogenously-induced DNA breaks through lineage-specific mechanisms. Further, this downregulation of D3 may be important for delaying S phase entry in response to DNA breaks, providing an additional mechanism to promote genome stability during lymphocyte development. Finally, I discovered novel roles of the HuR RNA-binding protein in regulating B cell function. Specifically, HuR is largely dispensable for B cell development and in vitro B cell function; however, it is crucial for the in vivo T cell-dependent immune response in mice, likely by facilitating the ability of B cells to interact with other immune cells in the follicular milieu. This work provides new insight into the lineage- and developmental stage-specific ways in which complex gene expression programs contribute to the normal development and function of B and T lymphocytes, while suppressing malignant transformation.