Novel richter syndrome xenograft models to study genetic architecture, biology, and therapy responses

Tiziana Vaisitti, Esteban D Braggio, John N. Allan, Francesca Arruga, Sara Serra, Alberto Zamo, Wayne Tam, Amy Chadburn, Richard R. Furman, Silvia Deaglio

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Richter syndrome represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B-cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemoimmunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft (PDX) models of Richter syndrome, RS9737 and RS1316. Richter syndrome xenografts were genetically, morphologically, and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed overactivation of the B-cell receptor, NFkB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of Richter syndrome represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.

Original languageEnglish (US)
Pages (from-to)3413-3420
Number of pages8
JournalCancer Research
Volume78
Issue number13
DOIs
StatePublished - Jul 1 2018

Fingerprint

Heterografts
Neoplasms
Therapeutics
RNA Sequence Analysis
Mutation
Lymphoma, Large B-Cell, Diffuse
Trisomy
B-Cell Chronic Lymphocytic Leukemia
Transcriptome
B-Lymphocytes
Phosphotransferases
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Novel richter syndrome xenograft models to study genetic architecture, biology, and therapy responses. / Vaisitti, Tiziana; Braggio, Esteban D; Allan, John N.; Arruga, Francesca; Serra, Sara; Zamo, Alberto; Tam, Wayne; Chadburn, Amy; Furman, Richard R.; Deaglio, Silvia.

In: Cancer Research, Vol. 78, No. 13, 01.07.2018, p. 3413-3420.

Research output: Contribution to journalArticle

Vaisitti, T, Braggio, ED, Allan, JN, Arruga, F, Serra, S, Zamo, A, Tam, W, Chadburn, A, Furman, RR & Deaglio, S 2018, 'Novel richter syndrome xenograft models to study genetic architecture, biology, and therapy responses', Cancer Research, vol. 78, no. 13, pp. 3413-3420. https://doi.org/10.1158/0008-5472.CAN-17-4004
Vaisitti, Tiziana ; Braggio, Esteban D ; Allan, John N. ; Arruga, Francesca ; Serra, Sara ; Zamo, Alberto ; Tam, Wayne ; Chadburn, Amy ; Furman, Richard R. ; Deaglio, Silvia. / Novel richter syndrome xenograft models to study genetic architecture, biology, and therapy responses. In: Cancer Research. 2018 ; Vol. 78, No. 13. pp. 3413-3420.
@article{66a58d1a841045b8a0b585a76c9f327a,
title = "Novel richter syndrome xenograft models to study genetic architecture, biology, and therapy responses",
abstract = "Richter syndrome represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B-cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemoimmunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft (PDX) models of Richter syndrome, RS9737 and RS1316. Richter syndrome xenografts were genetically, morphologically, and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80{\%} of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed overactivation of the B-cell receptor, NFkB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of Richter syndrome represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.",
author = "Tiziana Vaisitti and Braggio, {Esteban D} and Allan, {John N.} and Francesca Arruga and Sara Serra and Alberto Zamo and Wayne Tam and Amy Chadburn and Furman, {Richard R.} and Silvia Deaglio",
year = "2018",
month = "7",
day = "1",
doi = "10.1158/0008-5472.CAN-17-4004",
language = "English (US)",
volume = "78",
pages = "3413--3420",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

TY - JOUR

T1 - Novel richter syndrome xenograft models to study genetic architecture, biology, and therapy responses

AU - Vaisitti, Tiziana

AU - Braggio, Esteban D

AU - Allan, John N.

AU - Arruga, Francesca

AU - Serra, Sara

AU - Zamo, Alberto

AU - Tam, Wayne

AU - Chadburn, Amy

AU - Furman, Richard R.

AU - Deaglio, Silvia

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Richter syndrome represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B-cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemoimmunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft (PDX) models of Richter syndrome, RS9737 and RS1316. Richter syndrome xenografts were genetically, morphologically, and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed overactivation of the B-cell receptor, NFkB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of Richter syndrome represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.

AB - Richter syndrome represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B-cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemoimmunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft (PDX) models of Richter syndrome, RS9737 and RS1316. Richter syndrome xenografts were genetically, morphologically, and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed overactivation of the B-cell receptor, NFkB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of Richter syndrome represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.

UR - http://www.scopus.com/inward/record.url?scp=85049247979&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049247979&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-17-4004

DO - 10.1158/0008-5472.CAN-17-4004

M3 - Article

C2 - 29735551

AN - SCOPUS:85049247979

VL - 78

SP - 3413

EP - 3420

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 13

ER -