The Role of Polycomb Repressive Complexes 1 in Diffuse Large B-cell Lymphoma
von Débora Joppi
Datum der mündl. Prüfung:2024-11-29
Erschienen:2025-10-24
Betreuer:Dr. Björn Chapuy
Gutachter:Prof. Dr. Matthias Dobbelstein
Gutachter:Prof. Dr. Argyris Papantonis
Gutachter:Prof. Dr. Elisabeth Hessmann
Gutachter:Prof. Dr. Dieter Kube
Zum Verlinken/Zitieren:
http://dx.doi.org/10.53846/goediss-11570
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Zusammenfassung
Englisch
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell non-Hodgkin lymphoma, known for its molecular heterogeneity. It includes transcriptomic-based subtypes, i.e. germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes. Recent genomic classification identified five distinct genetic subtypes of DLBCL, namely C1-C5 DLBCLs, with C3 and C4 being enriched in GCB transcriptional subtypes. C3 and C4 DLBCLs are characterized, among other factors, by alterations in chromatin regulators, including gain-of-function mutations in the Polycomb Repressive Complex 2 (PRC2) component EZH2 and in linker and core histones, respectively. PRC2 has been described as a crucial factor in normal B-cell development, and the oncogenic activation of PRC2 by gain-of-function EZH2 mutations promotes lymphomagenesis by repressing genes involved in differentiation and cell cycle control. The connection between PRC2 and Polycomb Repressive Complex 1, particularly Polycomb Repressive Complex 1.1 (PRC1.1), exists in many contexts and has also been described in naïve B cells. Given the common and well-studied EZH2 mutations in DLBCL, I asked whether other Polycomb group proteins are also frequently mutated. In a large and informative dataset of more than 800 primary DLBCLs, I identified several subunits of the PRC1.1 complex that harbor likely loss-of-function mutations. I hypothesized that the PRC1.1 plays a tumor-suppressive role in DLBCL and that its dysfunction contributes to disease progression. Genetic analyses revealed recurrent mutations affecting PRC1.1 subunits, particularly USP7, enriched in GCB-like subtypes. Functional studies indicated that mutations in USP7 impair the half-life of USP7 and its interaction with other PRC1.1 components, such as BCOR and PCGF1, leading to destabilization of the complex. Moreover, overexpression of PCGF1 in DLBCL cell lines resulted in increased levels of H2AK119Ub, a hallmark of PRC1 activity, suggesting that PRC1.1-mediated gene repression is compromised in the presence of these mutations. Given the cooperative role of PRC1.1 with EZH2 and BCL6 in maintaining gene repression during B-cell development, along with the frequent mutations observed in PRC1.1 subunits in DLBCL, and the underexplored role of PRC1 in B-cell lymphoma, this study aimed to investigate the specific role of PRC1.1 in DLBCL. The findings from this project support a tumor-suppressive role for PRC1.1 in DLBCL, particularly through its regulatory functions on chromatin dynamics. The disruption of PRC1.1 appears to play an important role in specific DLBCL subtypes, contributing to the deregulation of gene expression and disease progression. Ongoing studies will reveal the transcriptional targets of PRC1.1. These strategies could lead to treatments designed to prevent or reverse the oncogenic effects of PRC1.1 dysregulation, potentially improving outcomes for patients with refractory or relapsed DLBCL.
Keywords: Diffuse Large B-cell Lymphoma; Polycomb Repressive Complex 1
Schlagwörter: Polycomb Repressive Complex 1; Diffuse Large B-cell Lymphoma
