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.
Bibliographical noteFunding Information:
The authors would like to thank the Biomedical Genomics Center at the University of Minnesota (Minneapolis, MN) for performing the Illumina deep sequencing. We also acknowledge the following shared resources of the Masonic Cancer Center at the University of Minnesota: The Mouse Genetics Laboratory, Biostatistics and Bioinformatics, Flow Cytometry Resource, and Comparative Pathology. We thank the Minnesota Supercomputing Institute for computational resources. We thank the Research Animal Resources at the University of Minnesota, specifically Alwan Aliye, for his technical support in mouse maintenance. This work received funding from the American Cancer Society Research Professor Award and NIH-NCI CA113636 (to D.A. Largaespada) the NIH-NINDS-P50 N5057531, and the Margaret Harvey Schering Trust. M.A. Farrar was funded by NIH R01 CA151845 and CA154998. T.K. Starr was supported by funding from the NIH NCI (5R00CA151672-04) and the Masonic Cancer Center NIH support grant (P30-CA77598).
M.A. Farrar reports receiving a commercial research grant from Merck. D.A. Largaespada is the co-founder/co-owner of NeoClone Biotechnologies, Inc., Discovery Genomics, Inc., and B-MoGen Biotechnologies, Inc., is a consultant for Surrogen,Inc.,andreportsreceivingfundingfromGenentech,Inc.B.S.Moriarityis the co-founder and the chief scientific officer for B-MoGen Biotechnologies. No potential conflicts of interest were disclosed by the other authors.
© 2018 American Association for Cancer Research.