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 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.
authors.affiliation: Institute for Research in Immunology and Cancer and Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC, Canada;
authors.forename: Biljana
authors.initials: B
authors.lastname: Culjkovic-Kraljacic
authors.affiliation: Hematology and Oncology Division.
authors.forename: Tharu M
authors.initials: TM
authors.lastname: Fernando
authors.affiliation: Hematology and Oncology Division.
authors.forename: Rossella
authors.initials: R
authors.lastname: Marullo
authors.affiliation: Hematology and Oncology Division.
authors.forename: Nieves
authors.initials: N
authors.lastname: Calvo-Vidal
authors.affiliation: Department of Physiology and Biophysics, Institute for Computational Biomedicine, and.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Verma
authors.affiliation: Hematology and Oncology Division.
authors.forename: ShaoNing
authors.initials: S
authors.lastname: Yang
authors.affiliation: Pathology and Laboratory Medicine Department, Weill Cornell Medical College, Cornell University, New York, NY; Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Turin, Italy;
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tabbò
authors.affiliation: Pathology and Laboratory Medicine Department, Weill Cornell Medical College, Cornell University, New York, NY;
authors.forename: Marcello
authors.initials: M
authors.lastname: Gaudiano
authors.affiliation: Institute for Research in Immunology and Cancer and Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC, Canada;
authors.forename: Hiba
authors.initials: H
authors.lastname: Zahreddine
authors.affiliation: Hematology and Oncology Division.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Goldstein
authors.affiliation: Hematology and Oncology Division.
authors.forename: Jayeshkumar
authors.initials: J
authors.lastname: Patel
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY; and.
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY; and.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Turin, Italy; Division of Hematology, Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ladetto
authors.affiliation: Division of Hematology, Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ghione
authors.affiliation: Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Turin, Italy;
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Machiorlatti
authors.affiliation: Department of Physiology and Biophysics, Institute for Computational Biomedicine, and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Pathology and Laboratory Medicine Department, Weill Cornell Medical College, Cornell University, New York, NY;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: Hematology and Oncology Division.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Institute for Research in Immunology and Cancer and Department of Pathology and Cell Biology, Université de Montréal, Montréal, QC, Canada;
authors.forename: Katherine L B
authors.initials: KL
authors.lastname: Borden
authors.affiliation: Hematology and Oncology Division.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm