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Defining AP4-regulated gene expression programs in pro/pre-B cells overexpressing c-MYC

ABSTRACT: A hallmark feature of adaptive immune cells is their capacity for rapid cell proliferation required for producing and expanding cells with a diverse repertoire of antigen receptor and amplification of antigen-specific receptors. While proliferation is beneficial for host protection from infection and cancers, it inevitably elevates the risk of oncogenic transformation. Developing lymphocytes, as well as B cells in the germinal center (GC), are considered tumor-prone due to additional genomic insults from physiological antigen receptor gene rearrangement and editing. However, oncogenic transformation of lymphocytes is relatively rare, perhaps owing to an intrinsic, tumor-suppressive program. Here, we show that c-MYC not only facilitates rapid cell proliferation but, unexpectedly, also engages a counteracting tumor suppressive program through its downstream transcription factor, AP4. Haploinsufficiency for AP4 dramatically accelerates MYC-driven tumorigenesis in a B cell-intrinsic manner. At a mechanistic level, AP4 suppresses Erg, which is required for B cell development but also oncogenic, in MYC+ developing B cells, and thus AP4 restricts simultaneous expression of multiple oncogenic factors during B cell development. Thus, c-MYC has dual action that permit proliferative expansion of B cell precursors, while concurrently safeguarding against their transformation via engagement of an AP4-dependent, tumor-suppressive program.

ORGANISM(S): Mus musculus

PROVIDER: GSE133514 | GEO | 2021/06/19

REPOSITORIES: GEO

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Project description:Background: TP53, the most frequently mutated gene in human cancers, orchestrates a complex transcriptional program crucial for cancer prevention. While certain TP53-dependent genes have been extensively studied, others, like the recently identified RNF144B, remained poorly understood. This E3 ubiquitin ligase has shown potent tumor suppressor activity in murine Eμ Myc-driven lymphoma, emphasizing its significance in the TP53 network. However, little is known about its targets and its role in cancer development, requiring further exploration. In this work, we investigate RNF144B's impact on tumor suppression beyond the hematopoietic compartment in human cancers. Methods: Employing TP53 wild-type cells, we generated models lacking RNF144B in both non-transformed and cancerous cells of human and mouse origin. By using proteomics, transcriptomics, and functional analysis, we assessed RNF144B's impact in cellular proliferation and transformation. Through In vitro and in vivo experiments, we explored proliferation, transformation potential, DNA repair, cell cycle control, mitotic progression, and treatment resistance. Findings were contrasted with clinical datasets and bioinformatics analysis. Results: Our research underscores RNF144B's pivotal role as a tumor suppressor, particularly in lung adenocarcinoma. In both human and mouse oncogene-expressing cells, RNF144B deficiency heightened cellular proliferation and transformation. Proteomic and transcriptomic analysis revealed RNF144B's novel function in mediating protein degradation associated with cell cycle progression, DNA damage response and genomic stability. RNF144B deficiency induced chromosomal instability, mitotic defects, and correlated with elevated aneuploidy and worse prognosis in human tumors. Furthermore, RNF144B-deficient lung adenocarcinoma cells exhibited resistance to cell cycle inhibitors that induce chromosomal instability. Conclusions: PRJNA1092607Supported by clinical data, our study suggests that RNF144B plays a pivotal role in maintaining genomic stability during tumor suppression.

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Defining AP4-regulated gene expression programs in pro/pre-B cells overexpressing c-MYC

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