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

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.