Metabolism and Therapeutic Resistance In
Acute Myeloid Leukemia
The Toulouse Cancer Laboratory of Excellence is a project that aims to understand the genetic and non-genetic mechanisms of resistance and relapse in cancer.
of our research axis
Acute Myeloid Leukemia (AML) is a heterogeneous group of hematological malignancies resulting from the transformation of hematopoietic progenitors. Therapeutic resistance is the major reason of recurrence in AML patients and represents the main consequence of their unfavorable prognosis. The METAML team has shown that this resistance is initiated by cells whose mitochondria have a very high energy and oxidative activity (“OxPHOS”) after conventional chemotherapy but also after newly approved targeted therapies. We also demonstrated that this high mitochondrial activity is due to a metabolic adaptation set up by AML cells in response to mitochondrial stresses induced by the treatments. This leads to an increase in catabolic, energetic and reactive oxygen species (ROS) detoxification capacities, to a high flexibility to use different nutrients and to a greater dependence on mitochondrial NADH dehydrogenases (in particular NADH dehydrogenase of the respiratory chain complex I) Our studies have led to the filing of several patents on new molecular targets (e.g. CD39, CALCRL, ADM) whose inhibition allows sensitization of chemotherapy-resistant cells. More recently, our research has also led us to study the role of metabolic dialogue within the tumor and the host (JE. Sarry), transcriptional regulation and RNA splicing (M. Ghisi), as well as leukemic and host autophagy (C. Joffre) in the adaptive and metabolic mechanisms of therapeutic resistance. All this work is done in a strong preclinical (mouse and xenograft models with CREFRE; diets with ENVT, F. Granat) and clinical context in AML patients (S. Bertoli, V. DeMas, O. Rauzy, C. Récher, F. Vergez).
Acute myeloid leukemia
Metabolism and mitochondria
Transcriptional and post-transcriptional regulation
Role of metabolic dialogue and systemic metabolism in mitochondrial adaptation and therapeutic resistance of lam cells
Jean-Emmanuel Sarry & Fanny Grannat
Carine Joffre & Laura Poillet
PARTERNSHIPS & FUNDING
Centre de Recherches en Cancérologie de Toulouse (Oncopole)
Toulouse – FR
05 82 74 15 75
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