Exploiting the Metabolic Vulnerability of Leukemic Stem Cells (LSCs) in Inv(16) Acute Myeloid Leukemia (AML) with the Combination of Miristen, a Mir-126 Inhibitor, and Venetoclax

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.2953-2953
• Main Authors: Zhang, Lianjun, Hoang, Dinh Hoa, Kang, Hyunjun, Chen, Ying-Chieh, Fu, Yu-Hsuan, Pathak, Khyatiben V., Valerio, Melissa, Chen, Fang, Estrella, Katrina, Buettner, Ralf, Zhang, Bin, Pirrotte, Patrick, Marcucci, Guido, Kuo, Ya-Huei, Nguyen, Le Xuan Truong
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-186936

AML with inv(16)(p13q22) expresses the leukemogenic fusion gene CBFB-MYH11 and upregulates microRNA (miR)-126 that supports homeostasis, quiescence, and activity of LSCs. Genetic or pharmacologic depletion of miR-126 via miR-126 knock out (KO) or miRisten (a CpG-anti-miR-126 inhibitor) reduces LSCs in a Cbfb-MYH11 ( CM) knock-in (KI) AML model and inv(16) AML patient-derived xenografts (PDXs), respectively [PMID: 34686664]. However, the antileukemic underpinnings of miR-126 inhibition in inv(16) AML remain to be elucidated. LSCs reportedly rely on fatty acid metabolism/oxidative phosphorylation (OXPHOS) for their bioenergetic metabolic needs. To assess the role of miR-126 in metabolism, we performed metabolomic profiling for Lin-/c-Kit+ cells isolated from CM KI AML (miR-126 high) mice and CM with miR-126 KO mice ( CM/miR-126 Δ/Δ). Our data revealed that CM/miR-126 Δ/Δ had a significant decrease of short, medium as well as long-chain acyl carnitines and fatty acid (2 to 11 fold, p