Gene expression of viable human AML cells purified by FACS from bone marrows of three AML PDX treated by PBS(vehicle) or cytarabine

It has been hypothesized that chemotherapy resistant human acute myeloid leukemia (AML) cells are enriched in an immature phenotype, cellular quiescence and leukemic initiating cells (LICs). However, these hypotheses have never been validated completely in vivo. We have developed a physiologically relevant chemotherapeutic approach with cytosine arabinoside AraC using patient-derived xenograft (PDX) models. AraC-treated AML cells are not consistently enriched for either immature cells or quiescent cells. AraC treatment does not enrich for LICs as measured by limiting dilution in secondary transplantations. Rather chemotherapy resistant cells in vivo have high levels of reactive oxygen species (ROS) and a gene signature consistent with oxidative phosphorylation (OXPHOS). Treatment of human HIGH OXPHOS but not LOW OXPHOS AML cell lines showed chemotherapy resistance in vivo, showing that essential mitochondrial functions make significant contributions to AraC resistance in AML. Accordingly, targeting mitochondrial OXPHOS metabolism through the inhibition of mitochondrial protein synthesis, the electron transfer chain or fatty acid oxidation induced an energetic shift towards LOW OXPHOS and strongly enhanced anti-leukemic effects of AraC in AML cells. These results demonstrate that chemotherapy resistance in AML is not necessarily associated with stemness but is highly dependent on a distinct oxidative metabolism, and that the HIGH OXPHOS gene signature is a robust hallmark of the AraC response in PDX and a promising therapeutic avenue to treat AML residual disease.

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Farge T, Saland E, de Toni F, Aroua N, Hosseini M, Perry R, Bosc C, Sugita M, Stuani L, Fraisse M, Scotland S, Larrue C, Boutzen H, Féliu V, Nicolau-Travers ML, Cassant-Sourdy S, Broin N, David M, Serhan N, Sarry A, Tavitian S, Kaoma T, Vallar L, Iacovoni J, Linares LK, Montersino C, Castellano R, Griessinger E, Collette Y, Duchamp O, Barreira Y, Hirsch P, Palama T, Gales L, Delhommeau F, Garmy-Susini BH, Portais JC, Vergez F, Selak M, Danet-Desnoyers G, Carroll M, Récher C, Sarry JE