Pharmacological inhibition of miR-126 enhances venetoclax activity in acute myeloid leukemia

ABSTRACT: Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) depend on oxidative phosphorylation (OXPHOS) sustained by fatty acid oxidation (FAO) and mitochondrial fusion (mitofusion). In this study, we demonstrate that microRNA-126 (miR-126) maintains LSC function by promoting B-cell lymphoma 2 (BCL-2)-dependent FAO, OXPHOS, and mitofusion, whereas its inhibition disrupts mitochondrial metabolism, induces mitochondrial fission (mitofission), and triggers apoptosis. Mechanistically, miR-126 stabilizes BCL-2 through the SPRED1/extracellular signal-regulated kinase axis, which upregulates CPT1B (FAO) and NRF2 (antioxidant response) while regulating mitochondrial dynamics through DRP1 phosphorylation (inhibiting mitofission) and MFN1/2 phosphorylation (enhancing mitofusion). miRisten, a CpG-conjugated anti-miR-126 oligonucleotide now in clinical trials (NCT07025564), synergized with venetoclax (VEN) to suppress FAO/OXPHOS, promote mitofission, and impair LSC homeostasis. In vivo, miRisten potentiated the VEN/azacitidine regimen, an US Food and Drug Administration-approved therapy for older or unfit patients with AML, significantly prolonging survival in patient-derived xenograft models. VEN/miRisten combination also reduced LSC burden and restored VEN sensitivity, establishing miR-126 inhibition as a transformative therapeutic strategy for AML.