PURPOSE: The lymph node microenvironment promotes resistance to chemotherapy in chronic lymphocytic leukemia (CLL), partly through induction of BCL2 family prosurvival proteins. Currently available inhibitors do not target all BCL2 family prosurvival proteins and their effectiveness is also modified by proapoptotic BCL2 homology domain 3 (BH3) only protein expression. The goal of this study was to evaluate synergy between the eIF4E/eIF4G interaction inhibitor, 4EGI-1, and the BH3 mimetic, ABT-737. EXPERIMENTAL DESIGN: CLL cells were cultured in conditions to mimic the lymph node microenvironment. Protein synthesis and cap-complex formation were determined. Polysome association of mRNAs from BCL2 family survival genes was analyzed by translational profiling. The effects of 4EGI-1 and the BCL2/BCL2L1 antagonist, ABT-737, on CLL cell apoptosis were determined. RESULTS: Protein synthesis was increased approximately 6-fold by stromal cell/CD154 culture in a phosphoinositide 3-kinase α (PI3Kα)-specific manner and was reduced by 4EGI-1. PI3K inhibitors and 4EGI-1 also reduced cap-complex formation but only 4EGI-1 consistently reduced BCL2L1 and BCL2A1 protein levels. 4EGI-1, but not PI3K inhibitors or rapamycin, induced an endoplasmic reticulum stress response including proapoptotic NOXA and the translation inhibitor phosphorylated eIF2α. 4EGI-1 and ABT-737 synergized to cause apoptosis, independent of levels of prosurvival protein expression in individual patients. CONCLUSIONS: Overall protein synthesis and cap-complex formation are induced by microenvironment stimuli in CLL. Inhibition of the cap-complex was not sufficient to repress BCL2 family prosurvival expression, but 4EGI-1 inhibited BCL2A1 and BCL2L1 while inducing NOXA through cap-dependent and -independent mechanisms. 4EGI-1 and ABT-737 synergized to produce apoptosis, and these agents may be the basis for a therapeutically useful combination.
PURPOSE: The lymph node microenvironment promotes resistance to chemotherapy in chronic lymphocytic leukemia (CLL), partly through induction of BCL2 family prosurvival proteins. Currently available inhibitors do not target all BCL2 family prosurvival proteins and their effectiveness is also modified by proapoptotic BCL2 homology domain 3 (BH3) only protein expression. The goal of this study was to evaluate synergy between the eIF4E/eIF4G interaction inhibitor, 4EGI-1, and the BH3 mimetic, ABT-737. EXPERIMENTAL DESIGN: CLL cells were cultured in conditions to mimic the lymph node microenvironment. Protein synthesis and cap-complex formation were determined. Polysome association of mRNAs from BCL2 family survival genes was analyzed by translational profiling. The effects of 4EGI-1 and the BCL2/BCL2L1 antagonist, ABT-737, on CLL cell apoptosis were determined. RESULTS: Protein synthesis was increased approximately 6-fold by stromal cell/CD154 culture in a phosphoinositide 3-kinase α (PI3Kα)-specific manner and was reduced by 4EGI-1. PI3K inhibitors and 4EGI-1 also reduced cap-complex formation but only 4EGI-1 consistently reduced BCL2L1 and BCL2A1 protein levels. 4EGI-1, but not PI3K inhibitors or rapamycin, induced an endoplasmic reticulum stress response including proapoptotic NOXA and the translation inhibitor phosphorylated eIF2α. 4EGI-1 and ABT-737 synergized to cause apoptosis, independent of levels of prosurvival protein expression in individual patients. CONCLUSIONS: Overall protein synthesis and cap-complex formation are induced by microenvironment stimuli in CLL. Inhibition of the cap-complex was not sufficient to repress BCL2 family prosurvival expression, but 4EGI-1 inhibited BCL2A1 and BCL2L1 while inducing NOXA through cap-dependent and -independent mechanisms. 4EGI-1 and ABT-737 synergized to produce apoptosis, and these agents may be the basis for a therapeutically useful combination.
Authors: Evangelos Papadopoulos; Simon Jenni; Eihab Kabha; Khuloud J Takrouri; Tingfang Yi; Nicola Salvi; Rafael E Luna; Evripidis Gavathiotis; Poornachandran Mahalingam; Haribabu Arthanari; Ricard Rodriguez-Mias; Revital Yefidoff-Freedman; Bertal H Aktas; Michael Chorev; Jose A Halperin; Gerhard Wagner Journal: Proc Natl Acad Sci U S A Date: 2014-07-21 Impact factor: 11.205
Authors: Erin E Gallagher; James M Song; Arya Menon; Lauren D Mishra; Alyah F Chmiel; Amanda L Garner Journal: J Med Chem Date: 2019-05-09 Impact factor: 7.446
Authors: Larissa Lezina; Ruth V Spriggs; Daniel Beck; Carolyn Jones; Kate M Dudek; Aleksandra Bzura; George D D Jones; Graham Packham; Anne E Willis; Simon D Wagner Journal: Blood Adv Date: 2018-08-14
Authors: Benjamin R E Harris; Defeng Wang; Ye Zhang; Marina Ferrari; Aniekan Okon; Margot P Cleary; Carston R Wagner; Da-Qing Yang Journal: Mol Cell Biol Date: 2018-04-30 Impact factor: 4.272
Authors: John Maringa Githaka; Namita Tripathi; Raven Kirschenman; Namrata Patel; Vrajesh Pandya; David A Kramer; Rachel Montpetit; Lin Fu Zhu; Nahum Sonenberg; Richard P Fahlman; Nika N Danial; D Alan Underhill; Ing Swie Goping Journal: Nat Commun Date: 2021-05-19 Impact factor: 14.919
Authors: Zeeshan Ahmad; Blake A Jacobson; Mitchell W McDonald; Nicolas Vattendahl Vidal; Gabriel Vattendahl Vidal; Sierra Chen; Maxwell Dillenburg; Aniekan M Okon; Manish R Patel; Carston R Wagner; Robert A Kratzke Journal: Cancer Chemother Pharmacol Date: 2020-01-23 Impact factor: 3.333