Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin

Assouline, Sarit; Čuljković, Biljana; Cocolakis, Eftihia; Rousseau, Caroline; Beslu, Nathalie; Amri, Abdellatif; Caplan, Stephen; Leber, Brian; Roy, Denis‐Claude; Miller, Wilson H.; Borden, Katherine L. B.

doi:10.1182/blood-2009-02-205153

Cited by 277 publications

(407 citation statements)

References 17 publications

(23 reference statements)

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“…Although the number of patients in this preliminary trial were low (n ¼ 11), one complete and two partial responders were observed. 152 The Em-Myc mouse lymphoma model has been used to evaluate the roles of many of the important genes in the PI3K/ PTEN/Akt/mTOR pathway in their abilities to interact and enhance lymphomagenesis and result in sensitivity to targeted therapies. Elevated active Akt (Akt-Myr þ ) expression accelerated Em-Myc-induced lymphomagenesis and promoted chemotherapeutic drug resistance and sensitivity to rapamycin in Em-Myc mice.…”

Section: Pi3k/pten/akt/mtor Drug Resistance and Leukemia Therapymentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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Section: Pi3k/pten/akt/mtor Drug Resistance and Leukemia Therapymentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…Mutation of the cap-binding site of eIF4E impairs its activities in translation, mRNA export, and oncogenic transformation (12). Targeting the eIF4E-cap complex with a competitive m 7 G cap inhibitor is a promising strategy to generate anticancer agents (13,14). One such inhibitor, ribavirin, has reached clinical trials where it was used in poor-prognosis leukemia patients.…”

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confidence: 99%

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Osborne

Volpon

Kornblatt

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Recognition of the methyl-7-guanosine (m 7 G) cap structure on mRNA is an essential feature of mRNA metabolism and thus gene expression. Eukaryotic translation initiation factor 4E (eIF4E) promotes translation, mRNA export, proliferation, and oncogenic transformation dependent on this cap-binding activity. eIF4E-cap recognition is mediated via complementary charge interactions of the positively charged m 7 G cap between the negative π-electron clouds from two aromatic residues. Here, we demonstrate that a variant subfamily, eIF4E3, specifically binds the m 7 G cap in the absence of an aromatic sandwich, using instead a different spatial arrangement of residues to provide the necessary electrostatic and van der Waals contacts. Contacts are much more extensive between eIF4E3-cap than other family members. Structural analyses of other cap-binding proteins indicate this recognition mode is atypical. We demonstrate that eIF4E3 relies on this cap-binding activity to act as a tumor suppressor, competing with the growthpromoting functions of eIF4E. In fact, reduced eIF4E3 in high eIF4E cancers suggests that eIF4E3 underlies a clinically relevant inhibitory mechanism that is lost in some malignancies. Taken together, there is more structural plasticity in cap recognition than previously thought, and this is physiologically relevant.M etabolism of mRNA is a complex and highly regulated process dependent on the association of the methyl-7-guanosine (m 7 G) cap structure on the 5′ end of transcripts with appropriate proteins (1-3). In mammalian cells, the two major cap-binding proteins are the nuclear cap-binding complex (CBC) (4) and eukaryotic translation initiation factor 4E (eIF4E) (3). Specific cap recognition is key for the fate of transcripts and impacts processes such as mRNA processing and bulk mRNA export via the CBC or the nuclear export of specific transcripts as well as bulk translation by eIF4E (5). NMR and crystallographic studies reveal that m 7 G cap is specifically recognized by both the CBC and eIF4E via intercalation of the m 7 G cap moiety with the side chains of two aromatic residues, i.e., an aromatic sandwich (4, 6-9). This is an electrostatically driven process relying on the partial positive charge of the m 7 G cap and the negative π-electron clouds of the aromatic residues. The aromatic residues are completely conserved in these cap-binding proteins. This recognition motif is used almost exclusively by proteins that specifically bind the m 7 G cap including eIF4E, CBC, and vaccinia virus protein VP39 (4, 10).Dysregulation of cap-binding proteins can have striking physiological consequences. For instance through its cap-binding activity and subsequent effects on gene expression, eIF4E plays an important role in proliferation and survival (1, 3). Indeed, eIF4E is overexpressed in about 30% of human cancers and its overexpression is oncogenic in cell culture and animal models (2, 11). Mutation of the cap-binding site of eIF4E impairs its activities in translation, mRNA export, and oncogenic transform...

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“…The generic antiviral ribavirin also inhibits oncogenic eIF4E activity and has been tested in an investigator-led Phase II trial in patients with acute myelogenous leukemia (AML). 11,12 The researchers reported 5 responses and 4 cases of stable disease among 11 evaluable patients.…”

Section: By Kai-jye Lou Staff Writermentioning

confidence: 99%

Translating autism

Lou¹

2012

Science-Business eXchange

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Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin

Cited by 277 publications

References 17 publications

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Translating autism

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