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Title: CD40L/IL-4-stimulated CLL demonstrates variation in translational regulation of DNA damage response genes including ATM.
Authors: Lezina, L
Spriggs, RV
Beck, D
Jones, C
Dudek, KM
Bzura, A
Jones, GDD
Packham, G
Willis, AE
Wagner, SD
First Published: 6-Aug-2018
Publisher: American Society of Hematology
Citation: Blood Advances, 2018, 2 (15), pp. 1869-1881
Abstract: 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.
DOI Link: 10.1182/bloodadvances.2017015560
eISSN: 2473-9537
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2018, American Society of Hematology. Deposited with reference to the publisher’s open access archiving policy. (
Description: The full-text version of this article contains a data supplement.
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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