AI Article Synopsis

  • - The study focuses on the role of leukaemia stem cells (LSCs) in the aggressiveness of mixed-lineage leukaemia (MLL) rearranged acute myeloid leukaemia (AML) and explores the interaction between the DNA damage response (DDR) and DOT1L/H3K79me pathways in maintaining LSCs.
  • - It was found that the enzyme ATM (part of the DDR) regulates LSC maintenance through a series of protein modifications, which includes phosphorylating CBP, helping it avoid degradation, and subsequently, acetylating DOT1L to boost expression of leukaemia-related genes.
  • - Interestingly, the ATM's regulatory effects on the CBP-DOT1

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178498PMC
http://dx.doi.org/10.1038/s41388-024-02998-2DOI Listing

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