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Hyperfunctioning MYC selectively redirects expression programs during human plasma cell differentiation II

ABSTRACT: MYC acts as a rheostat during plasma cell (PC) differentiation, linking B-cell activation to cell growth and division. Tight control over MYC is an essential feature of the network controlling differentiation. Deregulation of MYC is common in aggressive B-cell neoplasms, driving cellular transformation, and is often accompanied by apoptotic protection conferred by BCL2. Here we assess how acutely enforced MYC and BCL2 deregulation impacts on the ability of human B-cells to complete PC differentiation. In the context of a permissive state for PC differentiation such acute deregulation does not suffice to transform human B-cells. Instead MYC drives a sequence of metabolic and growth-related expression programs while suppressing the transition to immunoglobulin secretion and thus establishes an aberrant differentiation state. The ability of MYC to establish this aberrant state depends on MB0 and MBII of its transactivation domain. Dependence on MBII is profound and can be resolved to conserved residue W135.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262805 | GEO | 2025/07/22

REPOSITORIES: GEO

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Project description:MYC translocations are the biologic hallmark of Burkitt lymphomas but also occur in other mature B-cell lymphomas. If accompanied by chromosomal breaks targeting the BCL2 and/or BCL6 oncogenes, these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas (DHLs); otherwise, the term single-hit lymphoma (SHL) is applied. In order to characterize the biologic features of these MYC+ lymphomas other than Burkitt lymphomas, we explored, after exclusion of molecular Burkitt lymphoma (mBL) as defined by gene expression profiling (GEP), the molecular, pathological and clinical aspects of 80 MYC translocation (MYC+) lymphomas (31 SHL, 26 BCL2+/MYC+, 14 BCL6+/MYC+, 6 BCL2+/BCL6+/MYC+ and 3 MYC+ lymphomas with unknown BCL6 status). Comparison of SHL and DHL revealed no difference in frequency of MYC partner (IG/non-IG), genomic complexity or MYC expression and no differences in GEP. DHL showed a more frequent GCB-like GEP and higher IGH and MYC mutation rates. GEP revealed 130 differentially expressed genes between BCL6+/MYC+ and BCL2+/MYC+ DHL. BCL2+/MYC+ DHL showed a more frequent GCB-like GEP. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In contrast to mBL and lymphomas without MYC break, SHL and DHL patients had similar poor outcome. Our data suggest that after excluding mBL, MYC+ lymphomas could be biologically widely lumped without further need for subclassification. 32 diffuse large B-cell lymphoma samples were hybridized to HG-U133A Affymetrix GeneChips. In addition, this study contains 30 already published samples, which contribute to GSE4475 (Hummel et al. 2006 (PMID 16760442)), as well as 18 already published samples from GSE22470 (Salaverria et al. 2011 (PMID 21487109)). No re-normalisation of the published samples was performed. The complete dataset representing: (1) the 32 diffuse large B-cell lymphoma Samples, (2) the 30 Samples from GSE4475 and (3) the 18 Samples from GSE22470, is linked below as a supplementary file

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Hyperfunctioning MYC selectively redirects expression programs during human plasma cell differentiation II

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