Integrative analyses reveal outcome-associated and targetable molecular partnerships between TP53, BRD4, TNFRSF10B, and CDKN1A in diffuse large B-cell lymphoma

AbstractDiffuse large B-cell lymphoma (DLBCL) is a common, genomically heterogenous disease that presents a clinical challenge despite the success of frontline regimens and second-line chimeric antigen receptor T-cell (CAR-T) therapy. Recently, genomic alterations and tumor microenvironment features associated with poor CAR-T response have been identified, namely those to theTP53 tumor suppressor gene. This retrospective analysis aimed to integrate various data to identify genomic partnerships capable of providing further clarity and actionable treatment targets within this population. Publicly available data were analyzed for differential expression based onTP53 and 24-month event-free survival (EFS24) status, revealing enrichments of the BRD4 bromodomain oncogene (p< 0.0001,p = 0.001). High-BRD4 andTP53 alterations were significantly associated with lower CDKN1A (p21) and TNFRSF10B (TRAIL-R2), a key tumor suppressor and CAR-T modulator, respectively. Significant loss of CD8 T-cell presence within low-TNFRSF0B (p = 0.0042) and altered-TP53 (p = 0.0424) patients showcased relevant outcome-associated tumor microenvironment features. Furthermore, reduced expression of CDKN1A was associated with low TNFRSF10B (FDR< 0.0001) and increased BRD4 interactant genes (FDR< 0.0001). Promisingly, in vitro MDM2 inhibition with Idasnutlin and TP53 reactivation via Eprenetapopt was able to renew TNFRSF10B protein expression. Additionally, applying the BRD4-degrading PROTAC ARV-825 a...
Source: Annals of Hematology - Category: Hematology Source Type: research