Transcriptomic classification of diffuse large B-cell lymphoma identifies a high-risk activated B-cell-like subpopulation with targetable MYC dysregulation

Matthew E. Stokes, Kerstin Wenzl, C. Chris Huang, María Ortiz, Chih-Chao Hsu, Matthew J. Maurer, Nicholas Stong, Yumi Nakayama, Lei Wu, Hsiling Chiu, Ann Polonskaia, Samuel A. Danziger, Fadi Towfic, Joel Parker, Rebecca L. King, Brian K. Link, Susan L. Slager, Vivekananda Sarangi, Yan W. Asmann, Joseph P. Novak, Akshay Sudhindra, Stephen M. Ansell, Thomas M. Habermann, Patrick R. Hagner, Grzegorz S. Nowakowski, James R. Cerhan, Anne J. Novak and Anita K. Gandhi ()
Additional contact information
Matthew E. Stokes: Bristol Myers Squibb
Kerstin Wenzl: Mayo Clinic
C. Chris Huang: Bristol Myers Squibb
María Ortiz: Bristol Myers Squibb
Chih-Chao Hsu: Bristol Myers Squibb
Matthew J. Maurer: Mayo Clinic
Nicholas Stong: Bristol Myers Squibb
Yumi Nakayama: Bristol Myers Squibb
Lei Wu: Bristol Myers Squibb
Hsiling Chiu: Bristol Myers Squibb
Ann Polonskaia: Bristol Myers Squibb
Samuel A. Danziger: Amazon
Fadi Towfic: Prometheus Biosciences
Joel Parker: Research Triangle Park
Rebecca L. King: Mayo Clinic
Brian K. Link: University of Iowa
Susan L. Slager: Mayo Clinic
Vivekananda Sarangi: Mayo Clinic
Yan W. Asmann: Mayo Clinic
Joseph P. Novak: Mayo Clinic
Akshay Sudhindra: Bristol Myers Squibb
Stephen M. Ansell: Mayo Clinic
Thomas M. Habermann: Mayo Clinic
Patrick R. Hagner: Bristol Myers Squibb
Grzegorz S. Nowakowski: Mayo Clinic
James R. Cerhan: Mayo Clinic
Anne J. Novak: Mayo Clinic
Anita K. Gandhi: Bristol Myers Squibb

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Immunochemotherapy has been the mainstay of treatment for newly diagnosed diffuse large B-cell lymphoma (ndDLBCL) yet is inadequate for many patients. In this work, we perform unsupervised clustering on transcriptomic features from a large cohort of ndDLBCL patients and identify seven clusters, one called A7 with poor prognosis, and develop a classifier to identify these clusters in independent ndDLBCL cohorts. This high-risk cluster is enriched for activated B-cell cell-of-origin, low immune infiltration, high MYC expression, and copy number aberrations. We compare and contrast our methodology with recent DLBCL classifiers to contextualize our clusters and show improved prognostic utility. Finally, using pre-clinical models, we demonstrate a mechanistic rationale for IKZF1/3 degraders such as lenalidomide to overcome the low immune infiltration phenotype of A7 by inducing T-cell trafficking into tumors and upregulating MHC I and II on tumor cells, and demonstrate that TCF4 is an important regulator of MYC-related biology in A7.

Date: 2024
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DOI: 10.1038/s41467-024-50830-y

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