MRD is a new therapeutic target in AML

concurrently decreases CPT1B, FAO, and OXPHOS.These data reveal a novel link between a miR and the apoptotic/metabolic circuitry of AML LSCs and provide a molecular rationale for combining miR-126 blockade with BCL-2 inhibitors.Importantly, this study demonstrated that miRisten-mediated pharmacologic inhibition of miR-126 synergizes with VEN to eliminate AML cells.The VEN/ miRisten combination suppresses FAO and OXPHOS to a far greater extent than either agent alone, leading to markedly enhanced apoptosis in LSCenriched blasts.Notably, this synergy persists in VEN-resistant LSCs, whereas normal hematopoietic progenitors are relatively spared, providing a therapeutic window for selectively targeting AML LSCs.More importantly, using preclinical animal models, Zhang et al demonstrated that miRisten can boost the FDA-approved VEN/azacitidine (VEN/ AZA) regimen, producing significantly longer survival than VEN or AZA alone across diverse AML subtypes, including inv( 16), FLT3-ITD, NPM1, and TP53 mutants.These rigorous in vivo results, spanning genetically distinct models and patient-derived xenografts, underscore the translational potential of this approach.Indeed, miRisten itself is headed toward the clinic with completed toxicology studies, emphasizing the immediate translational potential of this study's findings.In summary, Zhang et al established that miR-126 induces a critical metabolic switch in LSCs and provides compelling proof-of-principle for targeting it.By tuning mitochondrial fate, miR-126 inhibition rendered AML cells susceptible to VEN-mediated killing.This work lays the foundation for clinical exploration of VEN/AZA plus anti-miR-126 therapy to crack the metabolic armor of refractory AML LSCs.If successful, such a strategy could represent a significant advance in overcoming VEN resistance in AML.