Journal article
Transcriptomic classification of diffuse large B-cell lymphoma identifies a high-risk activated B-cell-like subpopulation with targetable MYC dysregulation
Nature communications, Vol.15(1), 6790
08/08/2024
DOI: 10.1038/s41467-024-50830-y
PMCID: PMC11310352
PMID: 39117654
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.Researchers identified 7 biological group of diffuse large B-cell lymphoma, one with poor prognosis. They developed a gene expression classifier to detect these groups, potentially improving prognosis and future treatments for the high-risk patients.
Details
- Title: Subtitle
- Transcriptomic classification of diffuse large B-cell lymphoma identifies a high-risk activated B-cell-like subpopulation with targetable MYC dysregulation
- Creators
- Matthew E Stokes - Bristol-Myers SquibbKerstin Wenzl - Mayo Clinic in ArizonaC. Chris Huang - Bristol-Myers SquibbMaría OrtizChih-Chao Hsu - Bristol-Myers SquibbMatthew J Maurer - Mayo Clinic in FloridaNicholas Stong - Bristol-Myers SquibbYumi Nakayama - Bristol-Myers SquibbLei Wu - Bristol-Myers SquibbHsiling Chiu - Bristol-Myers SquibbAnn Polonskaia - Bristol-Myers SquibbSamuel A Danziger - AmazonFadi Towfic - Prometheus BiosciencesJoel Parker - TriangleRebecca L King - Mayo Clinic in ArizonaBrian K Link - University of IowaSusan L Slager - Mayo Clinic in FloridaVivekananda Sarangi - Mayo Clinic in ArizonaYan W Asmann - Mayo Clinic in FloridaJoseph P Novak - Mayo Clinic in ArizonaAkshay Sudhindra - Bristol-Myers SquibbStephen M Ansell - Mayo Clinic in ArizonaThomas M Habermann - Mayo Clinic in ArizonaPatrick R Hagner - Bristol-Myers SquibbGrzegorz S Nowakowski - Mayo Clinic in ArizonaJames R Cerhan - Mayo Clinic in ArizonaAnne J Novak - Mayo Clinic in ArizonaAnita K Gandhi - Bristol-Myers Squibb
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.15(1), 6790
- Publisher
- Nature Publishing Group
- DOI
- 10.1038/s41467-024-50830-y
- PMID
- 39117654
- PMCID
- PMC11310352
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Grant note
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI): SPORE-P50 CA97274, R01 CA212162-01A1, U01 CA195568
The authors thank Maria Wang and Scott Ely for technical assistance to the IHC data generation and interpretation. This work was supported in part by the NIH/NCI grants SPORE-P50 CA97274 (J.R. Cerhan and A.J. Novak), R01 CA212162-01A1 (A.J. Novak and J.R. Cerhan), U01 CA195568 (J.R. Cerhan), and the Predolin Foundation Biobank.DAS:Source data are provided as a Source Data file, found in the manuscript supplement. The sequencing data for the ROBUST clinical trial have been deposited in the EGA database under accession code EGAD50000000482. The data are available under restricted access, and can be applied for through the BMS FastTrack portal (https://fasttrack.bms.com/, hd-sci-apps@bms.com), which has an expected review time of 2-3 weeks. The ChIPseq data generated in this work are available on GEO under GSE267437. Additional data generated in this study are provided in the Supplementary Information/Source Data file. Source data are provided with this paper.
- Language
- English
- Date published
- 08/08/2024
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Internal Medicine
- Record Identifier
- 9984696659002771
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