Transcriptomic classification of diffuse large B-cell lymphoma identifies a high-risk activated B-cell-like...

Area of Science:

• Hematology
• Oncology
• Genomics
• Immunology

Background:

• Immunochemotherapy is standard for newly diagnosed diffuse large B-cell lymphoma (ndDLBCL), but treatment outcomes remain suboptimal for many patients.
• Identifying distinct molecular subtypes within ndDLBCL is crucial for refining prognostic assessments and therapeutic strategies.

Purpose of the Study:

• To perform unsupervised clustering of transcriptomic data from ndDLBCL patients to identify novel prognostic subgroups.
• To develop a classifier for identifying these molecular subtypes in independent patient cohorts.
• To investigate the biological characteristics and potential therapeutic vulnerabilities of identified high-risk clusters.

Main Methods:

• Unsupervised clustering analysis of gene expression profiles from a large cohort of ndDLBCL patients.
• Development and validation of a classifier to identify molecular clusters in independent datasets.
• Comparative analysis with existing DLBCL classifiers.
• Pre-clinical studies using in vitro and in vivo models to explore therapeutic rationales.

Main Results:

• Seven transcriptomic clusters were identified, including a poor-prognosis cluster designated A7.
• The A7 cluster is characterized by activated B-cell origin, low immune infiltration, high MYC expression, and copy number aberrations.
• The developed classifier demonstrated prognostic utility in independent cohorts.
• Pre-clinical models suggest IKZF1/3 degraders can enhance T-cell trafficking and MHC expression in A7 tumors, with TCF4 identified as a key regulator of MYC.

Conclusions:

• Transcriptomic profiling can delineate distinct prognostic subgroups in ndDLBCL, exemplified by the poor-risk A7 cluster.
• The A7 cluster presents a unique biological profile with potential therapeutic implications, particularly regarding immune evasion and MYC regulation.
• Targeting mechanisms that enhance immune infiltration, such as with IKZF1/3 degraders, may offer a strategy to overcome treatment resistance in this high-risk subgroup.