PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.

IF 21 1区 医学 Q1 HEMATOLOGY
Blood Pub Date : 2025-02-05 DOI:10.1182/blood.2024026040
Lingli He, Ting Zhao, Wei Zhong Leong, Azeem Sharda, Christina Mayerhofer, Shenglin Mei, Gracia M Bonilla, Juan Bautista Menendez-Gonzalez, Karin Gustafsson, Tsuyoshi Fukushima, Trine A Kristiansen, Ji-Won Lee, Yanxin Xu, Lei Chen, Jun Xia, Luis Angel Orozco, Bogdan Budnik, Ruslan Sadreyev, Zhixun Dou, David B Sykes, David T Scadden
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引用次数: 0

Abstract

Differentiation arrest and dependence on oxidative metabolism are features shared among genetically diverse acute myeloid leukemias (AML). A phenotypic CRISPR-Cas9 screen in AML identified dependence on phosphoseryl-tRNA kinase (PSTK), an atypical kinase required for the biosynthesis of all selenoproteins. In vivo, PSTK inhibition (PSTKi) impaired AML cell growth and leukemic stem cell self-renewal. Notably, timed pharmacologic PSTKi effectively targeted chemo-resistant AML in murine and patient-derived xenograft models, showing selectivity for malignant cells over normal hematopoietic cells. Mechanistically, PSTKi-induced reactive oxygen species (ROS) triggering mitochondrial DNA release into the cytosol and activated cGAS-STING. This activation in turn disrupted iron metabolism augmenting ROS generation and amplifying ferroptosis. Together, these findings reveal a self-reinforcing PSTK-cGAS-STING-ROS loop culminating in an oxidative crisis and ferroptotic cell death of leukemic stem cells. The data highlight the potential for augmenting standard cancer chemotherapies using timed metabolic intervention to eliminate chemopersisting cells and thereby impede disease relapse.

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来源期刊
Blood
Blood 医学-血液学
CiteScore
23.60
自引率
3.90%
发文量
955
审稿时长
1 months
期刊介绍: Blood, the official journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology and Immunotherapy scope; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Papers can be listed under more than one category as appropriate.
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