Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas Journal Article

Authors: Culjkovic-Kraljacic, B.; Fernando, T. M.; Marullo, R.; Calvo-Vidal, N.; Verma, A.; Yang, S.; Tabbò, F.; Gaudiano, M.; Zahreddine, H.; Goldstein, R. L.; Patel, J.; Taldone, T.; Chiosis, G.; Ladetto, M.; Ghione, P.; Machiorlatti, R.; Elemento, O.; Inghirami, G.; Melnick, A.; Borden, K. L. B.; Cerchietti, L.
Article Title: Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas
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 keymessengerRNA(mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to andmaintains 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 Hsp70mRNA 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. © 2016 by The American Society of Hematology. © 2016 by The American Society of Hematology.
Journal Title: Blood
Volume: 127
Issue: 7
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2016-02-18
Start Page: 858
End Page: 868
Language: English
DOI: 10.1182/blood-2015-05-645069
PROVIDER: scopus
PMCID: PMC4760090
PUBMED: 26603836
Notes: Article -- Export Date: 4 April 2016 -- Source: Scopus
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MSK Authors
  1. Gabriela Chiosis
    215 Chiosis
  2. Tony Taldone
    74 Taldone