Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation

  • Cell Stem Cell. 2025 Feb 17:S1934-5909(25)00013-X. doi: 10.1016/j.stem.2025.01.013.
Zemin Song  1 ,  Yali Cui  1 ,  Lilan Xin  2 ,  Ruijing Xiao  1 ,  Jingjing Feng  3 ,  Conghui Li  1 ,  Zhinang Yin  1 ,  Honghong Wang  1 ,  Qiuzi Li  1 ,  Mengxuan Wang  1 ,  Baoyi Lin  1 ,  Yiming Zhang  1 ,  Ying Zhou  1 ,  Li Huang  1 ,  Yanli He  4 ,  Xiaoqing Li  4 ,  Xiaoyan Liu  4 ,  Shangqin Liu  5 ,  Fuling Zhou  5 ,  Zheng Liu  3 ,  Hai-Bing Zhou  6 ,  Pingping Fang  7 ,  Kaiwei Liang  8
Affiliations
  • 1. State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 2. State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 3. The Institute for Advanced Studies, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 4. Center for Stem Cell Research and Application, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 5. Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
  • 6. State Key Laboratory of Virology and Biosafety, Frontier Science Center for Immunology and Metabolism, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
  • 7. State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
  • 8. State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
PMID: 39986274 DOI: 10.1016/j.stem.2025.01.013
Abstract

Mitochondria are integrated within the Cytoskeleton for structural integrity and functional regulation, yet the pathological exploitation of these interactions in cell fate decisions remains largely unexplored. Here, we identify a cytoskeleton-mitochondria remodeling mechanism underlying leukemic transformation by the core-binding factor subunit beta and smooth muscle Myosin heavy-chain fusion (CBFβ-SMMHC). This chimera reconstructs a cytosolic filamentous Cytoskeleton, inducing NMIIA phosphorylation and INF2-dependent filamentous actin (F-actin) assembly, which enhance cellular stiffness and tension, leading to calcium-mediated mitochondrial constriction, termed cytoskeletal co-option of mitochondrial constriction (CCMC). CCMC can also be triggered through diverse approaches independent of CBFβ-SMMHC, reconstructing a similar Cytoskeleton and recapitulating acute myeloid leukemia (AML) with consistent immunophenotypes and inflammatory signatures. Notably, CCMC generates TOM20-PDH+mtDNA+ mitochondrial-derived vesicles that activate cGAS-STING signaling, with STING knockout abrogating CCMC-induced leukemogenesis. Targeted inhibition of CCMC or STING suppresses AML propagation while sparing normal hematopoiesis. These findings establish CCMC as an intrinsic mechano-oncogenic process linking genetic mutations with cytoskeletal remodeling to oncogenic transformation, highlighting its promise as a therapeutic target.

Keywords
CBFβ-SMMHC; CCMC; HSPCs; MDV; cGAS-STING signaling; cytoskeletal co-option of mitochondrial constriction; cytoskeleton; hematopoietic stem and progenitor cells; mitochondrial-derived vesicle.
Products