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Open Access 11-03-2025 | Diffuse Large B-Cell Lymphoma | Research

MYC networks associate with decreased CD8 T-cell presence in diffuse large B-cell lymphoma and may be addressed by the synergistic combination of AZD4573 and Selinexor – a preliminary analysis

Authors: Alison C. Rutz, Kennedee S. Weber, Aidan L. Forberg, Adam Nik, Jordan Unrau, Ainslee J. Hemmen, Michael Minicozzi, Keenan T. Hartert

Published in: Annals of Hematology

Abstract

Diffuse Large B-cell Lymphoma (DLBCL) is a genomically-heterogenous disease affecting over 70,000 patients per year 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, with MYC amplification emerging in new analyses. This retrospective analysis aimed to integrate various data to identify genomic partnerships capable of providing added clarity and actionable treatment targets within this population. Publicly-available data were analyzed for differential expression based on MYC, 24-month event-free survival (EFS24) status, and CAR-T response. Notable T-cell partner genes such as IL7R (FDR = 0.00150) and CD58 (FDR = 5.375E-06) and cell death mediators such as PDCD1LG2 (FDR = 4.061E-06) were significantly lost in patients with High/Altered MYC that also failed EFS24. CD8 T-cell presence was also significantly lower in High/Altered MYC de-novo patients (p = 0.00112) and CAR-T non-responders (p = 0.00835). De-novo patients with both High/Altered MYC and CD8 T-cell absence faced a significantly inferior survival compared to counterparts with only one factor or neither (p = 0.0226). rrDLBCL patients reflected similar oncogenic pathways associated with greater scRNA MYC expression. In vitro application of the CDK9 inhibitor AZD4573 and XPO1 inhibitor Selinexor significantly reduced DLBCL cell line viability as single agents and produced synergistic results when applied in combination. Our analysis presents key associations between the MYC oncogene and depleted TME presence capable of providing clarity within the evolving precision CAR-T treatment landscape.

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Title: MYC networks associate with decreased CD8 T-cell presence in diffuse large B-cell lymphoma and may be addressed by the synergistic combination of AZD4573 and Selinexor – a preliminary analysis
Authors: Alison C. Rutz
Kennedee S. Weber
Aidan L. Forberg
Adam Nik
Jordan Unrau
Ainslee J. Hemmen
Michael Minicozzi
Keenan T. Hartert
Publication date: 11-03-2025
Publisher: Springer Berlin Heidelberg
Keywords: Diffuse Large B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma
Published in: Annals of Hematology
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI: https://doi.org/10.1007/s00277-025-06298-x

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