Abstract
We previously showed that the formation of protein complexes between MYC and its partner MIZ1 (MYC-interacting zinc finger 1) is critically required for germinal center (GC) B cell expansion (Toboso-Navasa et. al., JEM 2020). MYC and MIZ1 are transcriptional activators; however, they can form a transcriptional repressor complex that represses MIZ1 target genes. High expression of MYC is commonly found in aggressive B cell lymphoma, most notably in Burkitt Lymphoma (BL) and in a fraction of Diffuse B cell lymphomas (DLBCLs). In DLBCL, MYC positivity is associated with poorer prognosis, especially when co-expressed with BCL2, and increased proliferative capacity. However, it remains unclear whether the requirement for MYC-MIZ1 complexes for cell expansion is retained in lymphoma, similar to what we observed in GC B cells.
We first investigated MIZ1 expression in primary samples of B cell lymphoma sub-types and found it to be ubiquitous in BL (100% of cases; 14/14), whereas virtually absent in low-grade Follicular Lymphoma (7% of cases, 4/58). Roughly 42% of DLBCL cases (36/85; ) co-expressed MYC and MIZ1 and that was associated with increased cell proliferation assessed by Ki67. To investigate the role of MYC-MIZ1 complexes in lymphomagenesis, we generated compound mutant mice overexpressing in GC B cells wild-type MYC or a MYC mutant that cannot interact with MIZ1 (MYC VD) in combination with PI3K. MYC VD cannot repress MIZ1 target genes but displays normal interaction with MAX and transcriptional activation. As shown previously (Sander et. al., Cancer Cell 2012) MYC synergised with PI3K for BL development; however, overexpression of MYC VD plus PI3K had significantly delayed disease development and developed instead plasma cell hyperplasia. Analysis of pre-tumoral cells by single cell RNAseq revealed massive expansion of a unique GC B cell cluster only in mice carrying MYC and PI3K and this cluster had the highest suppression of MYC-MIZ1 target genes among all GC B cell clusters.
Taken together, this data indicates that the fraction of cells in which MYC and MIZ1 are co-expressed represents a "sweet spot" for B cell lymphomagenesis; and that the transcriptional repressive complex formed by MYC and MIZ1 is crucial for GC B lymphomagenesis.
Toboso-Navasa: Benevolent AI: Current Employment. Calado: Myricx Pharma: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties: Cancer Treatments. WO patent WO 2020/128475 A1 (2020).
