PMID- 26773040
OWN - NLM
STAT- MEDLINE
DCOM- 20170619
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 127
IP  - 18
DP  - 2016 May 5
TI  - Diffuse large B-cell lymphoma patient-derived xenograft models capture the 
      molecular and biological heterogeneity of the disease.
PG  - 2203-13
LID - 10.1182/blood-2015-09-672352 [doi]
AB  - 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.
CI  - (c) 2016 by The American Society of Hematology.
FAU - Chapuy, Bjoern
AU  - Chapuy B
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
FAU - Cheng, Hongwei
AU  - Cheng H
AD  - Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC, Canada;
FAU - Watahiki, Akira
AU  - Watahiki A
AD  - Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC, Canada;
FAU - Ducar, Matthew D
AU  - Ducar MD
AD  - Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
FAU - Tan, Yuxiang
AU  - Tan Y
AD  - Section of Computational Biomedicine, Boston University School of Medicine, 
      Boston, MA;
FAU - Chen, Linfeng
AU  - Chen L
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
FAU - Roemer, Margaretha G M
AU  - Roemer MG
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
FAU - Ouyang, Jing
AU  - Ouyang J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
FAU - Christie, Amanda L
AU  - Christie AL
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
FAU - Zhang, Liye
AU  - Zhang L
AD  - Section of Computational Biomedicine, Boston University School of Medicine, 
      Boston, MA;
FAU - Gusenleitner, Daniel
AU  - Gusenleitner D
AD  - Section of Computational Biomedicine, Boston University School of Medicine, 
      Boston, MA;
FAU - Abo, Ryan P
AU  - Abo RP
AD  - Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
FAU - Farinha, Pedro
AU  - Farinha P
AD  - Department of Pathology and Laboratory Medicine and the Center for Lymphoid 
      Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
FAU - von Bonin, Frederike
AU  - von Bonin F
AD  - Department of Hematology and Oncology, Georg-August University Goettingen, 
      Goettingen, Germany; and.
FAU - Thorner, Aaron R
AU  - Thorner AR
AD  - Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
FAU - Sun, Heather H
AU  - Sun HH
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, MA.
FAU - Gascoyne, Randy D
AU  - Gascoyne RD
AD  - Department of Pathology and Laboratory Medicine and the Center for Lymphoid 
      Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
FAU - Pinkus, Geraldine S
AU  - Pinkus GS
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, MA.
FAU - van Hummelen, Paul
AU  - van Hummelen P
AD  - Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
FAU - Wulf, Gerald G
AU  - Wulf GG
AD  - Department of Hematology and Oncology, Georg-August University Goettingen, 
      Goettingen, Germany; and.
FAU - Aster, Jon C
AU  - Aster JC
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, MA.
FAU - Weinstock, David M
AU  - Weinstock DM
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
FAU - Monti, Stefano
AU  - Monti S
AD  - Section of Computational Biomedicine, Boston University School of Medicine, 
      Boston, MA;
FAU - Rodig, Scott J
AU  - Rodig SJ
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, MA.
FAU - Wang, Yuzhuo
AU  - Wang Y
AD  - Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC, Canada;
FAU - Shipp, Margaret A
AU  - Shipp MA
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
LA  - eng
GR  - P01 CA092625/CA/NCI NIH HHS/United States
GR  - P42 ES007381/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160115
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
SB  - IM
MH  - Animals
MH  - Cell Lineage
MH  - Chromosome Aberrations
MH  - Gene Expression Regulation, Neoplastic
MH  - Genes, Neoplasm
MH  - Genetic Heterogeneity
MH  - Heterografts
MH  - Humans
MH  - Immunophenotyping
MH  - Lymphoma, Large B-Cell, Diffuse/*genetics/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, SCID
MH  - Mutation
MH  - Sequence Analysis, DNA
MH  - Subrenal Capsule Assay
MH  - Transcriptome
PMC - PMC4859195
EDAT- 2016/01/17 06:00
MHDA- 2017/06/20 06:00
PMCR- 2017/05/05
CRDT- 2016/01/17 06:00
PHST- 2015/09/28 00:00 [received]
PHST- 2016/01/11 00:00 [accepted]
PHST- 2016/01/17 06:00 [entrez]
PHST- 2016/01/17 06:00 [pubmed]
PHST- 2017/06/20 06:00 [medline]
PHST- 2017/05/05 00:00 [pmc-release]
AID - S0006-4971(20)30200-7 [pii]
AID - 2015/672352 [pii]
AID - 10.1182/blood-2015-09-672352 [doi]
PST - ppublish
SO  - Blood. 2016 May 5;127(18):2203-13. doi: 10.1182/blood-2015-09-672352. Epub 2016 
      Jan 15.