Marrow leptin-LEPR signaling rewires mitochondrial oxidative metabolism to confer chemoresistance in acute myeloid leukemia
Xinai Liao, Wei Dai, Xiaolin Xu, Danni Cai, Maoqing Tan, Zukai Wang, Yanrong Huang, Diyu Hou, Jingru Liu, Liuhuan Wang, Jin Wang, Xiaoting Wang, Shuxia Zhang, Xinjian Lin, Huifang Huang
TL;DR
High levels of leptin in bone marrow help leukemia cells resist chemotherapy by changing their energy use, and blocking leptin receptors can restore treatment effectiveness.
Contribution
Identifies a new metabolic mechanism of chemoresistance in AML driven by marrow leptin-LEPR signaling and shows that LEPR blockade can restore chemosensitivity.
Findings
Elevated marrow leptin and LEPR levels correlate with poor Ara-C clearance and reduced AML patient survival.
Leptin activates JAK2/STAT3 signaling, boosts mitochondrial activity, and protects blasts from drug-induced oxidative damage.
Blocking LEPR with Allo-aca restores chemosensitivity without affecting baseline leukemia growth.
Abstract
Leptin is abundant within marrow adipose tissue, yet its impact on acute myeloid leukemia (AML) therapy response is undefined. Here, we report that elevated bone-marrow leptin and blast-cell leptin-receptor (LEPR) levels strongly associate with poor cytarabine (Ara-C) clearance and reduced survival in newly diagnosed AML patients. Mechanistic and functional validation in human AML lines, primary blasts, and two syngeneic mouse models (MLL-AF9, AML1-ETO9a) shows that exogenous leptin markedly blunts Ara-C cytotoxicity, whereas the high-affinity LEPR antagonist Allo-aca restores chemosensitivity without altering baseline leukemia growth. Leptin up-regulates LEPR and triggers JAK2/STAT3 signaling that boosts mitochondrial complex Ⅰ activity, oxidative phosphorylation, and mitochondrial reactive oxygen species (mtROS); the resulting mtROS surge activates a compensatory antioxidant program…
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Taxonomy
TopicsAcute Myeloid Leukemia Research · Adipokines, Inflammation, and Metabolic Diseases · Regulation of Appetite and Obesity