CD40L/IL-4–stimulated CLL demonstrates variation in translational regulation of DNA damage response genes including ATM
| Autor: | Larissa Lezina, George D. D. Jones, Ruth V. Spriggs, Simon D. Wagner, Anne E. Willis, Carolyn J.P. Jones, Kate Dudek, Daniel O. Beck, Aleksandra Bzura, Graham Packham |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Translational efficiency DNA damage CD40 Ligand Ataxia Telangiectasia Mutated Proteins Biology Histones 03 medical and health sciences Translational regulation Tumor Microenvironment Humans Ribosome profiling Gene Lymphoid Neoplasia Kinase Translation (biology) Hematology Leukemia Lymphocytic Chronic B-Cell Cell biology 030104 developmental biology Gamma Rays Rad50 Protein Biosynthesis Female Interleukin-4 Tumor Suppressor Protein p53 DNA Damage |
| Popis: | CD40L/interleukin-4 (IL-4) stimulation occurs in vivo in the tumor microenvironment and induces global translation to varying degrees in individuals with chronic lymphocytic leukemia (CLL) in vitro. However, the implications of CD40L/IL-4 for the translation of specific genes is not known. To determine the most highly translationally regulated genes in response to CD40L/IL-4, we carried out ribosome profiling, a next-generation sequencing method. Significant differences in the translational efficiency of DNA damage response genes, specifically ataxia‐telangiectasia–mutated kinase (ATM) and the MRE11/RAD50/NBN (MRN) complex, were observed between patients, suggesting different patterns of translational regulation. We confirmed associations between CD40L/IL-4 response and baseline ATM levels, induction of ATM, and phosphorylation of the ATM targets, p53 and H2AX. X-irradiation was used to demonstrate that CD40L/IL-4 stimulation tended to improve DNA damage repair. Baseline ATM levels, independent of the presence of 11q deletion, correlated with overall survival (OS). Overall, we suggest that there are individual differences in translation of specific genes, including ATM, in response to CD40L/IL-4 and that these interpatient differences might be clinically important. |
| Databáze: | OpenAIRE |
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