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

CD40L/IL-4–stimulated CLL demonstrates variation in translational regulation of DNA damage response genes including ATM
CD40L/IL-4–stimulated CLL demonstrates variation in translational regulation of DNA damage response genes including ATM
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.
2473-9529
1869–1881
Lezina, Larissa
682733fe-d07b-4161-bffe-6f29293df999
Spriggs, Ruth V.
9765c0e1-7aa3-47a1-8c7f-2603a2d8c556
Beck, Daniel
688606bd-c51e-4a84-9755-f0c31a469a9b
Jones, Carolyn
703422f1-a8b0-4400-8898-5aff9dcc9a54
Dudek, Kate M.
d7ef2901-7bf1-488e-b730-60f38e02f57e
Bzura, Aleksandra
53745ae2-69a2-4acc-b7f6-7dd440276382
Jones, George D.D.
fdac49ac-6bb7-4e41-9dca-94b3ae5b79c1
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Willis, Anne E.
70657c98-607d-4626-8bdf-1468e8653f98
Wagner, Simon D.
39ec1b3c-2102-4aec-a2ab-e55c8e6e1662
Lezina, Larissa
682733fe-d07b-4161-bffe-6f29293df999
Spriggs, Ruth V.
9765c0e1-7aa3-47a1-8c7f-2603a2d8c556
Beck, Daniel
688606bd-c51e-4a84-9755-f0c31a469a9b
Jones, Carolyn
703422f1-a8b0-4400-8898-5aff9dcc9a54
Dudek, Kate M.
d7ef2901-7bf1-488e-b730-60f38e02f57e
Bzura, Aleksandra
53745ae2-69a2-4acc-b7f6-7dd440276382
Jones, George D.D.
fdac49ac-6bb7-4e41-9dca-94b3ae5b79c1
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Willis, Anne E.
70657c98-607d-4626-8bdf-1468e8653f98
Wagner, Simon D.
39ec1b3c-2102-4aec-a2ab-e55c8e6e1662

Lezina, Larissa, Spriggs, Ruth V., Beck, Daniel, Jones, Carolyn, Dudek, Kate M., Bzura, Aleksandra, Jones, George D.D., Packham, Graham, Willis, Anne E. and Wagner, Simon D. (2018) CD40L/IL-4–stimulated CLL demonstrates variation in translational regulation of DNA damage response genes including ATM. Blood Advances, 2 (15), 1869–1881. (doi:10.1182/bloodadvances.2017015560).

Record type: Article

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.

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Accepted/In Press date: 6 July 2018
e-pub ahead of print date: 6 August 2018
Published date: 14 August 2018

Identifiers

Local EPrints ID: 424228
URI: http://eprints.soton.ac.uk/id/eprint/424228
ISSN: 2473-9529
PURE UUID: 17218ea0-8757-446a-9b0d-8630905f8652
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 05 Oct 2018 11:35
Last modified: 22 Nov 2021 02:45

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Contributors

Author: Larissa Lezina
Author: Ruth V. Spriggs
Author: Daniel Beck
Author: Carolyn Jones
Author: Kate M. Dudek
Author: Aleksandra Bzura
Author: George D.D. Jones
Author: Graham Packham ORCID iD
Author: Anne E. Willis
Author: Simon D. Wagner

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