Sleeping beauty screen identifies RREB1 and other genetic drivers in human B-cell lymphoma

Eric P. Rahrmann, Natalie K. Wolf, George M. Otto, Lynn M Heltemes Harris, Laura B. Ramsey, Jingmin Shu, Rebecca S LaRue, Michael A Linden, Sue Rathe, Tim Starr, Michael A Farrar, Branden S Moriarity, David A Largaespada

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common non-Hodgkin lymphomas distinguishable by unique mutations, chromosomal rearrangements, and gene expression patterns. Here, it is demonstrated that early B-cell progenitors express 2',3'-cyclicnucleotide 3' phosphodiesterase (CNP) and that when targeted with Sleeping Beauty (SB) mutagenesis, Trp53 R270H mutation or Pten loss gave rise to highly penetrant lymphoid diseases, predominantly follicular lymphoma and DLBCL. In efforts to identify the genetic drivers and signaling pathways that are functionally important in lymphomagenesis, SB transposon insertions were analyzed from splenomegaly specimens of SB-mutagenized mice (n = 23) and SB-mutagenized mice on a Trp53 R270H background (n = 7) and identified 48 and 12 sites with statistically recurrent transposon insertion events, respectively. Comparison with human data sets revealed novel and known driver genes for B-cell development, disease, and signaling pathways: PI3K-AKT-mTOR, MAPK, NFkB, and B-cell receptor (BCR). Finally, functional data indicate that modulating Rasresponsive element-binding protein 1 (RREB1) expression in human DLBCL cell lines in vitro alters KRAS expression, signaling, and proliferation; thus, suggesting that this protooncogene is a common mechanism of RAS/MAPK hyperactivation in human DLBCL. Implications: A forward genetic screen identified new genetic drivers of human B-cell lymphoma and uncovered a RAS/ MAPK-activating mechanism not previously appreciated in human lymphoid disease. Overall, these data support targeting the RAS/MAPK pathway as a viable therapeutic target in a subset of human patients with DLBCL.

Original languageEnglish (US)
Pages (from-to)567-582
Number of pages16
JournalMolecular Cancer Research
Volume17
Issue number2
DOIs
StatePublished - Feb 1 2019

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Beauty
Lymphoma, Large B-Cell, Diffuse
B-Cell Lymphoma
Carrier Proteins
Follicular Lymphoma
B-Lymphocytes
Mutation
B-Lymphoid Precursor Cells
Splenomegaly
Phosphoric Diester Hydrolases
Medical Genetics
Phosphatidylinositol 3-Kinases
Mutagenesis
Non-Hodgkin's Lymphoma
Gene Expression
Cell Line
Genes

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Sleeping beauty screen identifies RREB1 and other genetic drivers in human B-cell lymphoma. / Rahrmann, Eric P.; Wolf, Natalie K.; Otto, George M.; Heltemes Harris, Lynn M; Ramsey, Laura B.; Shu, Jingmin; LaRue, Rebecca S; Linden, Michael A; Rathe, Sue; Starr, Tim; Farrar, Michael A; Moriarity, Branden S; Largaespada, David A.

In: Molecular Cancer Research, Vol. 17, No. 2, 01.02.2019, p. 567-582.

Research output: Contribution to journalArticle

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abstract = "Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common non-Hodgkin lymphomas distinguishable by unique mutations, chromosomal rearrangements, and gene expression patterns. Here, it is demonstrated that early B-cell progenitors express 2',3'-cyclicnucleotide 3' phosphodiesterase (CNP) and that when targeted with Sleeping Beauty (SB) mutagenesis, Trp53 R270H mutation or Pten loss gave rise to highly penetrant lymphoid diseases, predominantly follicular lymphoma and DLBCL. In efforts to identify the genetic drivers and signaling pathways that are functionally important in lymphomagenesis, SB transposon insertions were analyzed from splenomegaly specimens of SB-mutagenized mice (n = 23) and SB-mutagenized mice on a Trp53 R270H background (n = 7) and identified 48 and 12 sites with statistically recurrent transposon insertion events, respectively. Comparison with human data sets revealed novel and known driver genes for B-cell development, disease, and signaling pathways: PI3K-AKT-mTOR, MAPK, NFkB, and B-cell receptor (BCR). Finally, functional data indicate that modulating Rasresponsive element-binding protein 1 (RREB1) expression in human DLBCL cell lines in vitro alters KRAS expression, signaling, and proliferation; thus, suggesting that this protooncogene is a common mechanism of RAS/MAPK hyperactivation in human DLBCL. Implications: A forward genetic screen identified new genetic drivers of human B-cell lymphoma and uncovered a RAS/ MAPK-activating mechanism not previously appreciated in human lymphoid disease. Overall, these data support targeting the RAS/MAPK pathway as a viable therapeutic target in a subset of human patients with DLBCL.",
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AU - Wolf, Natalie K.

AU - Otto, George M.

AU - Heltemes Harris, Lynn M

AU - Ramsey, Laura B.

AU - Shu, Jingmin

AU - LaRue, Rebecca S

AU - Linden, Michael A

AU - Rathe, Sue

AU - Starr, Tim

AU - Farrar, Michael A

AU - Moriarity, Branden S

AU - Largaespada, David A

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AB - Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common non-Hodgkin lymphomas distinguishable by unique mutations, chromosomal rearrangements, and gene expression patterns. Here, it is demonstrated that early B-cell progenitors express 2',3'-cyclicnucleotide 3' phosphodiesterase (CNP) and that when targeted with Sleeping Beauty (SB) mutagenesis, Trp53 R270H mutation or Pten loss gave rise to highly penetrant lymphoid diseases, predominantly follicular lymphoma and DLBCL. In efforts to identify the genetic drivers and signaling pathways that are functionally important in lymphomagenesis, SB transposon insertions were analyzed from splenomegaly specimens of SB-mutagenized mice (n = 23) and SB-mutagenized mice on a Trp53 R270H background (n = 7) and identified 48 and 12 sites with statistically recurrent transposon insertion events, respectively. Comparison with human data sets revealed novel and known driver genes for B-cell development, disease, and signaling pathways: PI3K-AKT-mTOR, MAPK, NFkB, and B-cell receptor (BCR). Finally, functional data indicate that modulating Rasresponsive element-binding protein 1 (RREB1) expression in human DLBCL cell lines in vitro alters KRAS expression, signaling, and proliferation; thus, suggesting that this protooncogene is a common mechanism of RAS/MAPK hyperactivation in human DLBCL. Implications: A forward genetic screen identified new genetic drivers of human B-cell lymphoma and uncovered a RAS/ MAPK-activating mechanism not previously appreciated in human lymphoid disease. Overall, these data support targeting the RAS/MAPK pathway as a viable therapeutic target in a subset of human patients with DLBCL.

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