TitleCombinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas.
Publication TypeJournal Article
Year of Publication2016
AuthorsCuljkovic-Kraljacic, Biljana, Fernando Tharu M., Marullo Rossella, Calvo-Vidal Nieves, Verma Akanksha, Yang ShaoNing, Tabbò Fabrizio, Gaudiano Marcello, Zahreddine Hiba, Goldstein Rebecca L., Patel Jayeshkumar, Taldone Tony, Chiosis Gabriela, Ladetto Marco, Ghione Paola, Machiorlatti Rodolfo, Elemento Olivier, Inghirami Giorgio, Melnick Ari, Borden Katherine L. B., and Cerchietti Leandro
JournalBlood
Volume127
Issue7
Pagination858-68
Date Published2016 Feb 18
ISSN1528-0020
KeywordsActive Transport, Cell Nucleus, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Cell Nucleus, Humans, Lymphoma, B-Cell, Neoplasm Proteins, RNA, Messenger, RNA, Neoplasm
Abstract

<p>Aggressive double- and triple-hit (DH/TH) diffuse large B-cell lymphomas (DLBCLs) feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls posttranscriptional dynamics of key messenger RNA (mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E. eIF4E drives nuclear export and translation of BCL6, MYC, and BCL2 mRNA. eIF4E RNA-immunoprecipitation sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes B-cell receptor signaling, cellular metabolism, and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes, DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counterregulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative antilymphoma activity in DH/TH DLBCL in vitro and in vivo. </p>

DOI10.1182/blood-2015-05-645069
Alternate JournalBlood
PubMed ID26603836
PubMed Central IDPMC4760090
Grant ListR01 80728 / / PHS HHS / United States
R56 CA098571 / CA / NCI NIH HHS / United States
UL1 RR024996 / RR / NCRR NIH HHS / United States
R01 CA155226 / CA / NCI NIH HHS / United States
R01 CA098571 / CA / NCI NIH HHS / United States
R0198571 / / PHS HHS / United States
R01 CA080728 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P01 CA186866 / CA / NCI NIH HHS / United States
R01 CA172546 / CA / NCI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States