New results on the mechanism of drug resistance in AML (Acute Myeloid Leukemia) published in Cancer Discovery by the Team RESISTAML (INSERM U1037) headed by Dr. Jean-Emmanuel Sarry, IMODI Partner

AACR 2017 - Poster presentation - Abstract # 3846 by Dr. Juan Iovanna (Inserm U1068, Marseille, France)
Poster presented by Dr. Juan Iovanna (Inserm U1068, Marseille, France) at the Annual AACR congress (USA, Washington, 1-6 April 2017)
07/04/2017
Olivier DUCHAMP, IMODI coordinator, co-author of the book: Patient Derived Tumor Xenograft Models
02/05/2017

New results on the mechanism of drug resistance in AML (Acute Myeloid Leukemia) published in Cancer Discovery by the Team RESISTAML (INSERM U1037) headed by Dr. Jean-Emmanuel Sarry, IMODI Partner

Chemotherapy Resistant Human Acute Myeloid Leukemia Cells are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism

Farge T1, Saland E1, de Toni F1, Aroua N1, Hosseini M1, Perry R2, Bosc C1, Sugita M2, Stuani L1, Fraisse M1, Scotland S1, Larrue C1, Boutzen H1, Féliu V1, Nicolau-Travers ML1, Cassant-Sourdy S3, Broin N1, David M1, Serhan N1, Sarry A4, Tavitian S4, Kaoma T5, Vallar L5, Iacovoni J3, Linares LK6, Montersino C7, Castellano R7, Griessinger E8, Collette Y7, Duchamp O9, Barreira Y10, Hirsch P11, Palama T12, Gales L12, Delhommeau F13, Garmy-Susini BH3, Portais JC12, Vergez F14, Selak M2, Danet-Desnoyers G2, Carroll M2, Récher C15, Sarry JE16.

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Abstract
Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSCs). To validate this hypothesis in vivo, we developed a clinically relevant chemotherapeutic approach treating patient-derived xenograft (PDX) with cytarabine. Cytarabine residual AML cells are enriched neither in immature, quiescent cells nor LSCs. Strikingly, cytarabine-resistant pre-existing and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. Cytarabine residual cells exhibited increased fatty acid oxidation, upregulated CD36 expression and a HIGH OXPHOS gene signature predictive for treatment response in PDX and AML patients. HIGH OXPHOS but not LOW OXPHOS human AML cell lines were chemoresistant in vivo. Targeting mitochondrial protein synthesis, electron transfer, or fatty acid oxidation induced an energetic shift towards LOW OXPHOS and markedly enhanced anti-leukemic effects of cytarabine. Together, this study demonstrates that essential mitochondrial functions contribute to cytarabine resistance in AML and are a robust hallmark of cytarabine sensitivity and a promising therapeutic avenue to treat AML residual disease.

Copyright ©2017, American Association for Cancer Research.

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