Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease

• Published in: Blood 2016-05, Vol.127 (18), p.2203-2213
• Main Authors: Chapuy, Bjoern, Cheng, Hongwei, Watahiki, Akira, Ducar, Matthew D., Tan, Yuxiang, Chen, Linfeng, Roemer, Margaretha G.M., Ouyang, Jing, Christie, Amanda L., Zhang, Liye, Gusenleitner, Daniel, Abo, Ryan P., Farinha, Pedro, von Bonin, Frederike, Thorner, Aaron R., Sun, Heather H., Gascoyne, Randy D., Pinkus, Geraldine S., van Hummelen, Paul, Wulf, Gerald G., Aster, Jon C., Weinstock, David M., Monti, Stefano, Rodig, Scott J., Wang, Yuzhuo, Shipp, Margaret A.
• Format: Article
• Language: English
• Subjects: Animals; Cell Lineage; Chromosome Aberrations; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Genetic Heterogeneity; Heterografts; Humans; Immunophenotyping; Lymphoid Neoplasia; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Sequence Analysis, DNA; Subrenal Capsule Assay; Transcriptome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-09-672352

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined by transcriptional classifications, specific signaling and survival pathways, and multiple low-frequency genetic alterations. Preclinical model systems that capture the genetic and functional heterogeneity of DLBCL are urgently needed. Here, we generated and characterized a panel of large B-cell lymphoma (LBCL) patient-derived xenograft (PDX) models, including 8 that reflect the immunophenotypic, transcriptional, genetic, and functional heterogeneity of primary DLBCL and 1 that is a plasmablastic lymphoma. All LBCL PDX models were subjected to whole-transcriptome sequencing to classify cell of origin and consensus clustering classification (CCC) subtypes. Mutations and chromosomal rearrangements were evaluated by whole-exome sequencing with an extended bait set. Six of the 8 DLBCL models were activated B-cell (ABC)-type tumors that exhibited ABC-associated mutations such as MYD88, CD79B, CARD11, and PIM1. The remaining 2 DLBCL models were germinal B-cell type, with characteristic alterations of GNA13, CREBBP, and EZH2, and chromosomal translocations involving IgH and either BCL2 or MYC. Only 25% of the DLBCL PDX models harbored inactivating TP53 mutations, whereas 75% exhibited copy number alterations of TP53 or its upstream modifier, CDKN2A, consistent with the reported incidence and type of p53 pathway alterations in primary DLBCL. By CCC criteria, 6 of 8 DLBCL PDX models were B-cell receptor (BCR)-type tumors that exhibited selective surface immunoglobulin expression and sensitivity to entospletinib, a recently developed spleen tyrosine kinase inhibitor. In summary, we have established and characterized faithful PDX models of DLBCL and demonstrated their usefulness in functional analyses of proximal BCR pathway inhibition. •Our generated PDX models reflect the immunophenotypic, transcriptional, genetic, and functional heterogeneity of primary DLBCL.•The experimental and analytical approach will inform the development of additional PDX models and facilitate preclinical drug discovery.