{"doi":"10.7936/y11b-av13","title":"Uncovering a MYC-driven Tumor-suppressive Program in Proliferating Lymphocytes","abstract":"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.","journal":"Open Scholarship Institutional Repository (Washington University in St. Louis)","year":2021,"id":227071,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9514,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":564290,"name":"Elena Tonc","orcid":"0000-0002-6604-6496","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:54:42.179886Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}