MYC/MIZ1 complex formation is essential in development of aggressive germinal center-derived lymphomas
King's College London (University of London), 2022
Online
Hochschulschrift
Zugriff:
MYC and MIZ1 complexes are known to be critically required in germinal center (GC) B cell expansion. Both MYC and MIZ1 are transcriptional activators but their interaction can form a transcriptional repressor complex that suppresses MIZ1 target genes. Aggressive B cell lymphomas are mainly derived from GC B cells and high MYC expression is commonly identified in these cancers, especially in Burkitt Lymphoma (BL) and in a fraction of Diffuse Large B cell lymphoma (DLBCL). MYC positivity in DLBCL, especially when co-expressed with B-cell lymphoma 2 (BCL2), is associated with poorer prognosis. However, it remains unclear currently whether MYC and MIZ1 complexes play a role in aggressive B cell lymphomagenesis. We first investigated MYC and MIZ1 expression in primary samples of B cell lymphoma sub-types. While MYC and MIZ1 co-expression was ubiquitous in BL, it was absent in low grade Follicular lymphoma. MYC and MIZ1 expression in DLBCL was heterogenous and 20% of the samples co-expressed MYC and MIZ1. We then analysed the gene expression profiles of DLBCLs from the publicly available ReMODL-B trial dataset and similarly found heterogenous expression of MYC and MIZ1. Around 30% of the samples co-expressed MYC and MIZ1 and they represented a distinct DLBCL phenotypic subtype as addition of Bortezomib onto standard R-CHOP chemotherapy improved survival solely in this group of patients. To investigate MYC-MIZ1 interaction in lymphomagenesis, we generated compound mutant mice overexpressing in GC B cells either wild-type MYC (MYC) or a mutant MYC (MYCVD) that cannot interact with MIZ1 in combination with PI3K; FFMYC PI3K and FFVD PI3K, respectively. MYCVD can interact with MAX resulting in transcriptional activation but does not have repressive function. As shown previously, MYC synergised with PI3K for BL development. However, overexpression of MYCVD plus PI3K led to significantly delayed disease development and plasma cell (PC) hyperplasia. Analysis of immunised pre-tumoral mice showed lower fraction of GC B cells associated with increased PC formation in FFVD PI3K compared to FFMYC PI3K, which was not attributable to cell proliferation or death. Additionally, we observed increased GC B cell confinement in FFVD PI3K. Single cell RNA-sequencing analysis of the pre- tumoral cells revealed branching pseudotime trajectories of GC B cells resulting in either differentiation into PC or retention in the GC reaction. Analysis of MYC and MIZ1 targets in GC B cells prior to fate branching identified several genes that were upregulated in FFVD PI3K including Gna13, Actr3, and Arpc5. As cytoskeleton remodelling and RhoA pathways were enriched in FFVD PI3K, we hypothesise MYC-MIZ1 complexes' regulation of actin polymerisation contributes to the preservation of GC B cells in the reaction in FFMYC PI3K. Taken together, this work indicates that MYC and MIZ1 interaction in the context of PI3K and MYC overexpression maintains GC phenotype and restricts PC differentiation. This emphasises the pivotal role this transcriptionally repressive complex in GC B cells and lymphomagenesis.
Titel: |
MYC/MIZ1 complex formation is essential in development of aggressive germinal center-derived lymphomas
|
---|---|
Autor/in / Beteiligte Person: | Gunawan, Arief ; Parente Calado, Dinis Pedro ; Spencer, Jo Michele |
Link: | |
Veröffentlichung: | King's College London (University of London), 2022 |
Medientyp: | Hochschulschrift |
Sonstiges: |
|