2. Academic Validation
  3. The DNA damage-independent ATM signalling maintains CBP/DOT1L axis in MLL rearranged acute myeloid leukaemia

The DNA damage-independent ATM signalling maintains CBP/DOT1L axis in MLL rearranged acute myeloid leukaemia

  • Oncogene. 2024 Apr 26. doi: 10.1038/s41388-024-02998-2.
Guangming Wang # 1 2 3,  Wenjun Zhang # 1,  Jie Ren # 4,  Yu Zeng # 5,  Xiuyong Dang 1,  Xiaoxue Tian 1,  Wenlei Yu 1,  Zheng Li 1,  Yuting Ma 1,  Pingping Yang 1,  Jinyuan Lu 1,  Junke Zheng 6 7,  Bing Lu 8,  Jun Xu 9,  Aibin Liang 10
Affiliations

Affiliations

  • 1 Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
  • 2 East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
  • 3 Postdoctoral Station of Clinical Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China.
  • 4 Eye & ENT Hospital, Fudan University, Shanghai, 200031, China.
  • 5 Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
  • 6 Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
  • 7 Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
  • 8 East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. [email protected].
  • 9 East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. [email protected].
  • 10 Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China. [email protected].
  • # Contributed equally.
PMID: 38671157 DOI: 10.1038/s41388-024-02998-2
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.

Figures
Products