The DNA Damage-independent ATM Signalling Maintains CBP/DOT1L Axis in MLL Rearranged Acute Myeloid Leukaemia

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2024 Apr 26

PMID 38671157

Authors

Guangming Wang

Wenjun Zhang

Jie Ren

Yu Zeng

Xiuyong Dang

Xiaoxue Tian

Wenlei Yu

Zheng Li

Yuting Ma

Pingping Yang

Jinyuan Lu

Junke Zheng

Bing Lu

Jun Xu

Aibin Liang

Affiliations

Soon will be listed here.

Abstract

The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.

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