Date of Award
Doctor of Philosophy (PhD)
Rapid cell proliferation is a hallmark feature of adaptive immune cells lymphocytes. It is essential for the establishment of diverse antigen receptor repertoires and amplification of antigen-specific immune responses. While such proliferation is beneficial for host protection from infections and cancers, it inevitably elevates the risk of oncogenic transformation. In developing and germinal center B lymphocytes, the risk is further increased by endogenous, genomic insults due to antigen receptor rearrangements and somatic mutations, with which expression of the proto-oncogene c-MYC is closely associated. Nonetheless, frequencies of cancers originated from B lymphocytes are relatively low, suggesting that they are protected from transformation through a putative tumor-suppressive program coupled with their cell proliferation. In this work, we found that the proliferative driver c-MYC not only facilitates rapid cell proliferation but also unexpectedly engages a counteracting tumor-suppressive program through its downstream protein TFAP4. Missense mutations of TFAP4, including loss of function variants, were detected in human lymphoid malignancies, particularly in 12% of Burkitt lymphomas driven by overexpression of c-MYC. Furthermore, B-ALL patients with c-MYC overexpression and reduced expression of TFAP4 had worse survival compared to patients with high TFAP4 expressing B-ALL. In mice, haploinsufficiency for AP4 drastically accelerated tumor development in MYC-driven B cell lymphoid tumor models in a cell-intrinsic manner. Mechanistically, TFAP4 restricted the expression of protooncogene Erg, which, together with c-MYC, is required for B cell development. The risk of transformation was thus limited by blocking inappropriate co-expression of the two oncogenic proteins. TFAP4-mediated restriction of Erg also ensured appropriate coupling of c-MYC-mediated proliferation and the loss of self-renewing capacity in developing B cells. Thus, c-MYC suppresses the stemness of B cell progenitors by inducing TFAP4 while driving proliferation, and this transcription factor cascade functions as a tumor suppressor module that safeguards against the transformation of developing B cells. Thus, c-MYC concurrently engages proliferative and tumor-suppressive programs in B lymphocytes.
Chair and Committee
Kenneth M. Murphy, Jeffrey J. Bednarski, Chyi-Song Hsieh, Jacqueline E. Payton,
Tonc, Elena, "Uncovering a MYC-driven Tumor-suppressive Program in Proliferating Lymphocytes" (2021). Arts & Sciences Electronic Theses and Dissertations. 2539.
Available for download on Saturday, July 29, 2023