TY - JOUR
T1 - Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase
AU - Steinhardt, James J.
AU - Peroutka, Raymond J.
AU - Mazan-Mamczarz, Krystyna
AU - Chen, Qing
AU - Houng, Simone
AU - Robles, Carol
AU - Barth, Rolf N.
AU - DuBose, Joseph
AU - Bruns, Brandon
AU - Tesoriero, Ronald
AU - Stein, Deborah
AU - Fang, Raymond
AU - Hanna, Nader
AU - Pasley, Jason
AU - Rodriguez, Carlos
AU - Kligman, Mark D.
AU - Bradley, Matthew
AU - Rabin, Joseph
AU - Shackelford, Stacy
AU - Dai, Bojie
AU - Landon, Ari L.
AU - Scalea, Thomas
AU - Livak, Ferenc
AU - Gartenhaus, Ronald B.
N1 - Publisher Copyright:
© 2014, American Society of Hematology. All rights reserved.
PY - 2014/12/11
Y1 - 2014/12/11
N2 - Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5′ untranslated region (UTR). Oncogenes with complex 5′UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5′UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G+ splenic B cells, fromwhichmost DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM+ B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas.
AB - Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5′ untranslated region (UTR). Oncogenes with complex 5′UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5′UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G+ splenic B cells, fromwhichmost DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM+ B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas.
UR - http://www.scopus.com/inward/record.url?scp=84919628705&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-07-589689
DO - 10.1182/blood-2014-07-589689
M3 - Article
C2 - 25320244
AN - SCOPUS:84919628705
SN - 0006-4971
VL - 124
SP - 3758
EP - 3767
JO - Blood
JF - Blood
IS - 25
ER -