Abstract
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. 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. 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. 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.
Highlights
Defects in apoptosis due to dysregulation of BCL2 family proteins are common in cancers and BCL2 homology domain 3 (BH3) mimetic drugs, such as ABT-263, which bind and inhibit antiapoptotic BCL2, and to a lesser extentAuthors' Affiliations: 1Department of Cancer Studies and Molecular Medicine and MRC Toxicology Unit, University of Leicester; and 2Department of Haematology, University Hospitals of Leicester, Leicester, United KingdomNote: Supplementary data for this article are available at Clinical Cancer Research Online.BCL2L1, are being trialed in lymphoid malignancies [1, 2]
Overall protein synthesis and cap-complex formation are induced by microenvironment stimuli in chronic lymphocytic leukemia (CLL)
These results showed that induction of capcomplex formation associated with an increase in overall protein synthesis and both were effects of culture with stromal cells/CD154
Summary
Defects in apoptosis due to dysregulation of BCL2 family proteins are common in cancers and BCL2 homology domain 3 (BH3) mimetic drugs, such as ABT-263, which bind and inhibit antiapoptotic BCL2, and to a lesser extentAuthors' Affiliations: 1Department of Cancer Studies and Molecular Medicine and MRC Toxicology Unit, University of Leicester; and 2Department of Haematology, University Hospitals of Leicester, Leicester, United KingdomNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).BCL2L1, are being trialed in lymphoid malignancies [1, 2]. Circulating chronic lymphocytic leukemia (CLL) cells express more BCL2 than normal B cells and in vitro leukemic cells are highly sensitive to ABT-737 [4, 7], but within lymph nodes leukemic cells express BCL2A1, BCL2L1 [9], and MCL1 [10], which promote resistance to this agent Induction of these proteins is likely to be due to signals from the lymph node microenvironment [11] and in support of this, CLL cells stimulated in vitro by the T-cell surface molecule, CD154 [9, 12] or through B-cell receptor crosslinking [13] reproduce these expression changes.
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