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

Autor: Stokes ME; Informatics and Predictive Sciences, Bristol Myers Squibb, Summit, NJ, USA., Wenzl K; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Huang CC; Translational Medicine Hematology, Bristol Myers Squibb, Summit, NJ, USA., Ortiz M; Informatics and Predictive Sciences, Bristol Myers Squibb, Seville, Spain., Hsu CC; Translational Medicine Hematology, Bristol Myers Squibb, Summit, NJ, USA., Maurer MJ; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Stong N; Informatics and Predictive Sciences, Bristol Myers Squibb, Summit, NJ, USA., Nakayama Y; Translational Medicine Hematology, Bristol Myers Squibb, Summit, NJ, USA., Wu L; Translational Medicine Hematology, Bristol Myers Squibb, Summit, NJ, USA., Chiu H; Translational Medicine Hematology, Bristol Myers Squibb, Summit, NJ, USA., Polonskaia A; Translational Medicine Hematology, Bristol Myers Squibb, Summit, NJ, USA., Danziger SA; BMS at the time the study was conducted, Amazon, Seattle, WA, USA., Towfic F; BMS at the time the study was conducted, Prometheus Biosciences, San Diego, CA, USA., Parker J; LifeEDIT Therapeutics, Research Triangle Park, Durham, NC, USA., King RL; Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Link BK; Division of Hematology, Oncology, Blood and Marrow Transplant, University of Iowa, Iowa City, IA, USA., Slager SL; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Sarangi V; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Asmann YW; Department of Health Science Research, Mayo Clinic, Jacksonville, FL, USA., Novak JP; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Sudhindra A; Clinical Research and Development, Bristol Myers Squibb, Summit, NJ, USA., Ansell SM; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Habermann TM; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Hagner PR; Translational Medicine Hematology, Bristol Myers Squibb, Summit, NJ, USA., Nowakowski GS; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Cerhan JR; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Novak AJ; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Gandhi AK; Translational Medicine Hematology, Bristol Myers Squibb, Summit, NJ, USA. anita.gandhi@bms.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 08; Vol. 15 (1), pp. 6790. Date of Electronic Publication: 2024 Aug 08.
DOI: 10.1038/s41467-024-50830-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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