1869.full.pdf (1.83 MB)
Download file

CD40L/IL-4-stimulated CLL demonstrates variation in translational regulation of DNA damage response genes including ATM.

Download (1.83 MB)
journal contribution
posted on 01.07.2019, 10:49 by L Lezina, RV Spriggs, D Beck, C Jones, KM Dudek, A Bzura, GDD Jones, G Packham, AE Willis, SD Wagner
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.

Funding

This work was supported in part by a grant from Bloodwise (14038) (A.E.W. and S.D.W.).

History

Citation

Blood Advances, 2018, 2 (15), pp. 1869-1881

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre

Version

VoR (Version of Record)

Published in

Blood Advances

Publisher

American Society of Hematology

eissn

2473-9537

Acceptance date

06/07/2018

Copyright date

2018

Available date

01/07/2019

Publisher version

http://www.bloodadvances.org/content/2/15/1869?sso-checked=true

Notes

The full-text version of this article contains a data supplement.

Language

en

Usage metrics

Categories

Keywords

Exports