Abstract

Chronic lymphocytic leukemia (CLL), the most common adult leukemia, remains incurable despite advancements in treatment regimens over the past decade. Several expression profile studies have been pursued to better understand CLL pathogenesis. However, these large-scale studies only provide information at the transcriptional level. To better comprehend the differential protein changes that take place in CLL, we performed a reverse-phase protein array (RPPA) analysis using 167 different antibodies on B-cell lysates from 18 CLL patients and 6 normal donors. From our analysis, we discovered an enrichment of protein alterations involved with mRNA translation, specifically upregulation of the translation initiator eIF4G and phosphorylation of the cap-dependent translation inhibitor 4E-BP1 at serine 65. Interestingly, 4E-BP1 phosphorylation occurred independently of AKT phosphorylation, suggesting a disconnect between PI3K/AKT pathway activation and 4E-BP1 phosphorylation. Based on these results, we treated primary CLL samples with NVP-BEZ235, a PI3K/mTOR dual inhibitor, and compared its apoptotic-inducing potential against the BTK inhibitor Ibrutinib and the PI3Kδ inhibitor Idelalisib. We demonstrated that treatment with NVP-BEZ235 caused greater apoptosis, greater apoptotic cleavage of eIF4G, and greater dephosphorylation of 4E-BP1 in primary CLL cells. Taken together, these results highlight the potential dependence of eIF4G overexpression and 4E-BP1 phosphorylation in CLL survival.

Highlights

  • Chronic lymphocytic leukemia (CLL) is a malignant disease characterized by the accumulation of monoclonal B cells that have escaped their regulated life cycle

  • We demonstrated that treatment with NVP-BEZ235 caused greater apoptosis, greater apoptotic cleavage of eukaryotic translation factor 4G (eIF4G), and greater dephosphorylation of 4E-binding protein 1 (4E-BP1) in primary CLL cells

  • We demonstrate that the AKT/mTOR-related proteins are altered in CLL, with significant alteration occurring in the downstream mRNA translational machinery proteins eukaryotic translation factor 4G and the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1)

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Summary

Introduction

Chronic lymphocytic leukemia (CLL) is a malignant disease characterized by the accumulation of monoclonal B cells that have escaped their regulated life cycle. Particular factors that contribute to the incurability of CLL are the inter- and intra-tumor heterogeneity that exists among CLL populations and the subclonal expansion of refractory CLL cells that can arise after initial chemotherapy treatment [2, 3] Based on these underlying characteristics of CLL, many large-scale www.impactjournals.com/oncotarget biomarker studies have focused on determining molecular features that would help provide potential predictive and prognostic power in treating this disease. These studies have typically relied on mRNA-based gene expression or DNA-based somatic mutation and CpG methylation analysis. Though the understanding of CLL pathobiology has been greatly enhanced by these large-scale gene studies, the limiting aspect that still remains in RNA or DNA-based profiling is the inability to provide clarity to the altered protein expression and signaling landscape in CLL

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