Acute myeloid leukemias are cancers of the blood and bone marrow that are difficult to treat today because of the resistance of cancer cells to therapy. Currently, the 5-year survival rate is only about 30-40% in patients under 60 and 20-25% in patients over 60.
Cancer cells have been found in recent years to increase their mitochondrial function, the main “powerhouse of the cell”, generating one and a half times more energy than a normal cell and giving them a significant metabolic advantage. Thus, the cells richest in mitochondria are those which resist chemotherapy the best.
The mechanism of action of this resistance has so far remained largely unknown. A team of researchers from the Toulouse Cancer Research Center (CRCT) (team of Jean-Emmanuel Sarry) in collaboration with the IUCT, French, Swiss and Luxembourgish teams decipher for the first time a mechanism explaining chemoresistance and open a new major therapeutic route likely to significantly improve the survival of patients with this cancer.
This study shows that CD39 ectonucleotidase is activated in cytarabine (Arac) resistant leukemia cells in vivo and in vitro in patients with acute myeloid leukemia. The high activity of CD39 promotes resistance to AraC by enhancing the mitochondrial activity of cells by regulating the transcriptional program of mitochondrial stress response. This intrinsic non-canonical function of CD39 was not yet known.
The use of anti-CD39 monoclonal antibodies is already the subject of clinical studies in France and the USA. The combination of this immunotherapeutic treatment with chemotherapy or other immunotherapies such as anti-PD1 (thus allowing the immune system to destroy the tumor by itself) would be a very promising avenue to explore. The results obtained by this study, financially supported for years by the Toulouse Cancer Health Foundation, the League for the Fight against Cancer, the Gael Association, the Occitanie region and the TOUCAN labex point to great hope in the fight against cancer of the blood.
Discover the published article :
Cancer Discov. 2020 Jul 8;CD-19-1008.doi: 10.1158/2159-8290.CD-19-1008. Online ahead of print.
Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia
Nesrine Aroua , Emeline Boet , Margherita Ghisi , Marie-Laure Nicolau-Travers , Estelle Saland , Ryan Gwilliam , Fabienne de Toni , Mohsen Hosseini , Pierre-Luc Mouchel , Thomas Farge , Claudie Bosc , Lucille Stuani , Marie Sabatier , Fetta Mazed , Clement Larrue , Latifa Jarrou , Sarah Gandarillas , Massimiliano Bardotti , Muriel Picard , Charlotte Syrykh , Camille Laurent , Mathilde Gotanegre , Nathalie Bonnefoy , Floriant Bellvert , Jean-Charles Portais , Nathalie Nicot , Francisco Azuaje , Tony Kaoma , Carine Joffre , Jerome Tamburini , Christian Recher , Francois Vergez , Jean-Emmanuel Sarry
Key words :
- Cytarabine
- Acute Myeloid leukemia
- Mitochondrial stress
Contact :
Jean Emmanuel Sarry
CRCT team 18 : RESIST@ML – RESIST@ML – Drug resistance and oncometabolism in acute myeloid leukemia
Mail : Jean-emmanuel.sarry@inserm.fr
