Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway
Abstract Accumulating evidence indicates the presence of cytoplasmic DNAs in various types of malignant cells, and its involvement in anti-cancer drug- or radiotherapy-mediated DNA damage response and replication stress. However, the pathophysiological roles of cytoplasmic DNAs in leukemias remain l...
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doaj-ab9d156c7775481dba83492281d3a1222021-03-28T11:05:00ZengNature Publishing GroupCell Death and Disease2041-48892021-03-0112411410.1038/s41419-021-03587-xCytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathwayTomohisa Baba0Takeshi Yoshida1Yamato Tanabe2Tatsunori Nishimura3Soji Morishita4Noriko Gotoh5Atsushi Hirao6Rikinari Hanayama7Naofumi Mukaida8Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa UniversityDepartment of Immunology, Graduate School of Medical Sciences, Kanazawa UniversityDivision of Molecular Bioregulation, Cancer Research Institute, Kanazawa UniversityDivision of Cancer Cell Biology, Cancer Research Institute, Kanazawa UniversityDepartment of Transfusion Medicine and Stem Cell Regulation, Juntendo University School of MedicineDivision of Cancer Cell Biology, Cancer Research Institute, Kanazawa UniversityNano Life Science Institute, Kanazawa UniversityDepartment of Immunology, Graduate School of Medical Sciences, Kanazawa UniversityDivision of Molecular Bioregulation, Cancer Research Institute, Kanazawa UniversityAbstract Accumulating evidence indicates the presence of cytoplasmic DNAs in various types of malignant cells, and its involvement in anti-cancer drug- or radiotherapy-mediated DNA damage response and replication stress. However, the pathophysiological roles of cytoplasmic DNAs in leukemias remain largely unknown. We observed that during hematopoietic stem cell transplantation (HSCT) in mouse myeloid leukemia models, double-stranded (ds)DNAs were constitutively secreted in the form of extracellular vesicles (EVs) from myeloid leukemia cells and were transferred to the donor cells to dampen their hematopoietic capabilities. Subsequent analysis of cytoplasmic DNA dynamics in leukemia cells revealed that autophagy regulated cytoplasmic dsDNA accumulation and subsequent redistribution into EVs. Moreover, accumulated cytoplasmic dsDNAs activated STING pathway, thereby reducing leukemia cell viability through reactive oxygen species (ROS) generation. Pharmaceutical inhibition of autophagosome formation induced cytoplasmic DNA accumulation, eventually triggering cytoplasmic DNA sensing pathways to exert cytotoxicity, preferentially in leukemia cells. Thus, manipulation of cytoplasmic dsDNA dynamics can be a novel and potent therapeutic strategy for myeloid leukemias.https://doi.org/10.1038/s41419-021-03587-x |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tomohisa Baba Takeshi Yoshida Yamato Tanabe Tatsunori Nishimura Soji Morishita Noriko Gotoh Atsushi Hirao Rikinari Hanayama Naofumi Mukaida |
spellingShingle |
Tomohisa Baba Takeshi Yoshida Yamato Tanabe Tatsunori Nishimura Soji Morishita Noriko Gotoh Atsushi Hirao Rikinari Hanayama Naofumi Mukaida Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway Cell Death and Disease |
author_facet |
Tomohisa Baba Takeshi Yoshida Yamato Tanabe Tatsunori Nishimura Soji Morishita Noriko Gotoh Atsushi Hirao Rikinari Hanayama Naofumi Mukaida |
author_sort |
Tomohisa Baba |
title |
Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway |
title_short |
Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway |
title_full |
Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway |
title_fullStr |
Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway |
title_full_unstemmed |
Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway |
title_sort |
cytoplasmic dna accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular dna sensing pathway |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-03-01 |
description |
Abstract Accumulating evidence indicates the presence of cytoplasmic DNAs in various types of malignant cells, and its involvement in anti-cancer drug- or radiotherapy-mediated DNA damage response and replication stress. However, the pathophysiological roles of cytoplasmic DNAs in leukemias remain largely unknown. We observed that during hematopoietic stem cell transplantation (HSCT) in mouse myeloid leukemia models, double-stranded (ds)DNAs were constitutively secreted in the form of extracellular vesicles (EVs) from myeloid leukemia cells and were transferred to the donor cells to dampen their hematopoietic capabilities. Subsequent analysis of cytoplasmic DNA dynamics in leukemia cells revealed that autophagy regulated cytoplasmic dsDNA accumulation and subsequent redistribution into EVs. Moreover, accumulated cytoplasmic dsDNAs activated STING pathway, thereby reducing leukemia cell viability through reactive oxygen species (ROS) generation. Pharmaceutical inhibition of autophagosome formation induced cytoplasmic DNA accumulation, eventually triggering cytoplasmic DNA sensing pathways to exert cytotoxicity, preferentially in leukemia cells. Thus, manipulation of cytoplasmic dsDNA dynamics can be a novel and potent therapeutic strategy for myeloid leukemias. |
url |
https://doi.org/10.1038/s41419-021-03587-x |
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