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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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Defining AP4- and MYC-regulated gene expression programs in germinal center B cells during cyclic re-entry

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