PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice

Julia Weber, Jorge de la Rosa, Carolyn S. Grove, Markus Schick, Lena Rad, Olga Baranov, Alexander Strong, Anja Pfaus, Mathias J. Friedrich, Thomas Engleitner, Robert Lersch, Rupert Öllinger, Michael Grau, Irene Gonzalez Menendez, Manuela Martella, Ursula Kohlhofer, Ruby Banerjee, Maria A. Turchaninova, Anna Scherger, Gary J. Hoffman & 21 others Julia Hess, Laura B. Kuhn, Tim Ammon, Johnny Kim, Günter Schneider, Kristian Unger, Ursula Zimber-Strobl, Mathias Heikenwälder, Marc Schmidt-Supprian, Fengtang Yang, Dieter Saur, Pentao Liu, Katja Steiger, Dmitriy M. Chudakov, Georg Lenz, Leticia Quintanilla-Martinez, Ulrich Keller, George S. Vassiliou, Juan Cadiñanos, Allan Bradley, Roland Rad

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.

Original languageEnglish
Article number1415
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

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B-Cell Lymphoma
genes
mice
Screening
chromatin
screening
genome
Genes
Cells
oncogenes
sequencing
regulators
metabolism
biology
Chromatin
Clustered Regularly Interspaced Short Palindromic Repeats
platforms
cancer
Genome
Neoplasm Genes

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Weber, Julia ; de la Rosa, Jorge ; Grove, Carolyn S. ; Schick, Markus ; Rad, Lena ; Baranov, Olga ; Strong, Alexander ; Pfaus, Anja ; Friedrich, Mathias J. ; Engleitner, Thomas ; Lersch, Robert ; Öllinger, Rupert ; Grau, Michael ; Menendez, Irene Gonzalez ; Martella, Manuela ; Kohlhofer, Ursula ; Banerjee, Ruby ; Turchaninova, Maria A. ; Scherger, Anna ; Hoffman, Gary J. ; Hess, Julia ; Kuhn, Laura B. ; Ammon, Tim ; Kim, Johnny ; Schneider, Günter ; Unger, Kristian ; Zimber-Strobl, Ursula ; Heikenwälder, Mathias ; Schmidt-Supprian, Marc ; Yang, Fengtang ; Saur, Dieter ; Liu, Pentao ; Steiger, Katja ; Chudakov, Dmitriy M. ; Lenz, Georg ; Quintanilla-Martinez, Leticia ; Keller, Ulrich ; Vassiliou, George S. ; Cadiñanos, Juan ; Bradley, Allan ; Rad, Roland. / PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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title = "PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice",
abstract = "B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.",
author = "Julia Weber and {de la Rosa}, Jorge and Grove, {Carolyn S.} and Markus Schick and Lena Rad and Olga Baranov and Alexander Strong and Anja Pfaus and Friedrich, {Mathias J.} and Thomas Engleitner and Robert Lersch and Rupert {\"O}llinger and Michael Grau and Menendez, {Irene Gonzalez} and Manuela Martella and Ursula Kohlhofer and Ruby Banerjee and Turchaninova, {Maria A.} and Anna Scherger and Hoffman, {Gary J.} and Julia Hess and Kuhn, {Laura B.} and Tim Ammon and Johnny Kim and G{\"u}nter Schneider and Kristian Unger and Ursula Zimber-Strobl and Mathias Heikenw{\"a}lder and Marc Schmidt-Supprian and Fengtang Yang and Dieter Saur and Pentao Liu and Katja Steiger and Chudakov, {Dmitriy M.} and Georg Lenz and Leticia Quintanilla-Martinez and Ulrich Keller and Vassiliou, {George S.} and Juan Cadi{\~n}anos and Allan Bradley and Roland Rad",
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Weber, J, de la Rosa, J, Grove, CS, Schick, M, Rad, L, Baranov, O, Strong, A, Pfaus, A, Friedrich, MJ, Engleitner, T, Lersch, R, Öllinger, R, Grau, M, Menendez, IG, Martella, M, Kohlhofer, U, Banerjee, R, Turchaninova, MA, Scherger, A, Hoffman, GJ, Hess, J, Kuhn, LB, Ammon, T, Kim, J, Schneider, G, Unger, K, Zimber-Strobl, U, Heikenwälder, M, Schmidt-Supprian, M, Yang, F, Saur, D, Liu, P, Steiger, K, Chudakov, DM, Lenz, G, Quintanilla-Martinez, L, Keller, U, Vassiliou, GS, Cadiñanos, J, Bradley, A & Rad, R 2019, 'PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice' Nature Communications, vol. 10, no. 1, 1415. https://doi.org/10.1038/s41467-019-09180-3

PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice. / Weber, Julia; de la Rosa, Jorge; Grove, Carolyn S.; Schick, Markus; Rad, Lena; Baranov, Olga; Strong, Alexander; Pfaus, Anja; Friedrich, Mathias J.; Engleitner, Thomas; Lersch, Robert; Öllinger, Rupert; Grau, Michael; Menendez, Irene Gonzalez; Martella, Manuela; Kohlhofer, Ursula; Banerjee, Ruby; Turchaninova, Maria A.; Scherger, Anna; Hoffman, Gary J.; Hess, Julia; Kuhn, Laura B.; Ammon, Tim; Kim, Johnny; Schneider, Günter; Unger, Kristian; Zimber-Strobl, Ursula; Heikenwälder, Mathias; Schmidt-Supprian, Marc; Yang, Fengtang; Saur, Dieter; Liu, Pentao; Steiger, Katja; Chudakov, Dmitriy M.; Lenz, Georg; Quintanilla-Martinez, Leticia; Keller, Ulrich; Vassiliou, George S.; Cadiñanos, Juan; Bradley, Allan; Rad, Roland.

In: Nature Communications, Vol. 10, No. 1, 1415, 01.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice

AU - Weber, Julia

AU - de la Rosa, Jorge

AU - Grove, Carolyn S.

AU - Schick, Markus

AU - Rad, Lena

AU - Baranov, Olga

AU - Strong, Alexander

AU - Pfaus, Anja

AU - Friedrich, Mathias J.

AU - Engleitner, Thomas

AU - Lersch, Robert

AU - Öllinger, Rupert

AU - Grau, Michael

AU - Menendez, Irene Gonzalez

AU - Martella, Manuela

AU - Kohlhofer, Ursula

AU - Banerjee, Ruby

AU - Turchaninova, Maria A.

AU - Scherger, Anna

AU - Hoffman, Gary J.

AU - Hess, Julia

AU - Kuhn, Laura B.

AU - Ammon, Tim

AU - Kim, Johnny

AU - Schneider, Günter

AU - Unger, Kristian

AU - Zimber-Strobl, Ursula

AU - Heikenwälder, Mathias

AU - Schmidt-Supprian, Marc

AU - Yang, Fengtang

AU - Saur, Dieter

AU - Liu, Pentao

AU - Steiger, Katja

AU - Chudakov, Dmitriy M.

AU - Lenz, Georg

AU - Quintanilla-Martinez, Leticia

AU - Keller, Ulrich

AU - Vassiliou, George S.

AU - Cadiñanos, Juan

AU - Bradley, Allan

AU - Rad, Roland

PY - 2019/12/1

Y1 - 2019/12/1

N2 - B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.

AB - B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.

UR - http://www.scopus.com/inward/record.url?scp=85063729846&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-09180-3

DO - 10.1038/s41467-019-09180-3

M3 - Article

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 1415

ER -