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Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas.
- Source :
-
Blood [Blood] 2016 Feb 18; Vol. 127 (7), pp. 858-68. Date of Electronic Publication: 2015 Nov 24. - Publication Year :
- 2016
-
Abstract
- 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.<br /> (© 2016 by The American Society of Hematology.)
- Subjects :
- Active Transport, Cell Nucleus drug effects
Cell Line, Tumor
Cell Nucleus pathology
Humans
Lymphoma, B-Cell pathology
Neoplasm Proteins metabolism
Antineoplastic Combined Chemotherapy Protocols pharmacology
Cell Nucleus metabolism
Lymphoma, B-Cell drug therapy
Lymphoma, B-Cell metabolism
Neoplasm Proteins antagonists & inhibitors
RNA, Messenger metabolism
RNA, Neoplasm metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 127
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 26603836
- Full Text :
- https://doi.org/10.1182/blood-2015-05-645069