TY - JOUR
T1 - Sleeping beauty screen identifies RREB1 and other genetic drivers in human B-cell lymphoma
AU - Rahrmann, Eric P.
AU - Wolf, Natalie K.
AU - Otto, George M.
AU - Heltemes-Harris, Lynn
AU - Ramsey, Laura B.
AU - Shu, Jingmin
AU - LaRue, Rebecca S.
AU - Linden, Michael A.
AU - Rathe, Susan K.
AU - Starr, Timothy K.
AU - Farrar, Michael A.
AU - Moriarity, Branden S.
AU - Largaespada, David A.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
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'-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.
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U2 - 10.1158/1541-7786.MCR-18-0582
DO - 10.1158/1541-7786.MCR-18-0582
M3 - Article
C2 - 30355676
AN - SCOPUS:85060931009
SN - 1541-7786
VL - 17
SP - 567
EP - 582
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 2
ER -
