title: Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Akira
authors.initials: A
authors.lastname: Watahiki
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ducar
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Linfeng
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Margaretha G M
authors.initials: MG
authors.lastname: Roemer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jing
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
authors.forename: Liye
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
authors.forename: Daniel
authors.initials: D
authors.lastname: Gusenleitner
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Abo
authors.affiliation: Department of Pathology and Laboratory Medicine and the Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Pedro
authors.initials: P
authors.lastname: Farinha
authors.affiliation: Department of Hematology and Oncology, Georg-August University Goettingen, Goettingen, Germany; and.
authors.forename: Frederike
authors.initials: F
authors.lastname: von Bonin
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Thorner
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Sun
authors.affiliation: Department of Pathology and Laboratory Medicine and the Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Geraldine S
authors.initials: GS
authors.lastname: Pinkus
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Paul
authors.initials: P
authors.lastname: van Hummelen
authors.affiliation: Department of Hematology and Oncology, Georg-August University Goettingen, Goettingen, Germany; and.
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Wulf
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002869:Chromosome Aberrations; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D018740:Genetic Heterogeneity; D064593:Heterografts; D006801:Humans; D016130:Immunophenotyping; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D017422:Sequence Analysis, DNA; D013370:Subrenal Capsule Assay; D059467:Transcriptome