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

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Abstract

Diffuse 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 the TP53 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 on TP53 and 24-month event-free survival (EFS24) status, revealing enrichments of the BRD4 bromodomain oncogene (p < 0.0001, p = 0.001). High-BRD4 and TP53 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 and the CDK4/6 inhibitor Abemaciclib as single-agents and in synergistic combination significantly reduced TP53-altered DLBCL cell line viability. Our analysis presents key associations within a genomic network of actionable targets capable of providing clarity within the evolving precision CAR-T treatment landscape.

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Data availability

Data generated or analyzed during this study are included in this published article (and its supplemental information files) or are available publicly. Reasonable requests for additional data may be sent to the corresponding author.

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Acknowledgements

The views expressed in the submitted article are those of the authors and not an official position of the institution or funder. Dr. Javeed Iqbal and Dr. Alyssa Bouska from the University of Nebraska Medical Center kindly gifted the DHL16, Karpas-422, Ly3, and U2932 cell lines. Dr. Anne Novak from the Mayo Clinic, Rochester kindly gifted the DHL6 cell line.

Funding

This study was supported by the MNSU Faculty Research Grant (Minnesota State Colleges and Universities system), MNSU Undergraduate Research Center Foundation grants, and the Minnesota State University Mankato faculty startup fund. The funding sources were not involved in the study design, collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

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  1. Department of Biological Sciences, Minnesota State University Mankato, Mankato, MN, 56001, USA

    Aidan L. Forberg, Jordan Unrau, Kennedee S. Weber, Alison C. Rutz, Shelby Lund, Jinda Guidinger, Andrew Pelzel, Jackson Hauge, Ainslee J. Hemmen & Keenan T. Hartert

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Author contributions are as follows: A.F., J. U., K.W., A.R., S.L., J.G., A.P., J. H., A.H., and K.T.H. performed investigations and analyses. K.T.H. and A.F. were responsible for revision. K.T.H. was responsible for conceptualization, data curation, formal analysis, funding acquisition, writing, and supervision.

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Correspondence to Keenan T. Hartert.

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Forberg, A.L., Unrau, J., Weber, K.S. et al. Integrative analyses reveal outcome-associated and targetable molecular partnerships between TP53, BRD4, TNFRSF10B, and CDKN1A in diffuse large B-cell lymphoma. Ann Hematol 103, 199–209 (2024). https://doi.org/10.1007/s00277-023-05478-x

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