Cytoplasmic DNA Accumulation Preferentially Triggers Cell Death of Myeloid Leukemia Cells by Interacting with Intracellular DNA Sensing Pathway

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2021 Mar 27

PMID 33771977

Citations 7

Authors

Tomohisa Baba

Takeshi Yoshida

Yamato Tanabe

Tatsunori Nishimura

Soji Morishita

Noriko Gotoh

Atsushi Hirao

Rikinari Hanayama

Naofumi Mukaida

Affiliations

Soon will be listed here.

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.

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