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

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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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'-cyclic-nucleotide 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, NFκB, and B-cell receptor (BCR). Finally, functional data indicate that modulating Ras-responsive element-binding protein 1 (RREB1) expression in human DLBCL cell lines in vitro alters KRAS expression, signaling, and proliferation; thus, suggesting that this proto-oncogene 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
Issue number2
StatePublished - Feb 2019

Bibliographical note

Publisher Copyright:
© 2018 American Association for Cancer Research.

PubMed: MeSH publication types

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


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