Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells

Clément Larrue, Nathan Guiraud, Pierre-Luc Mouchel, Marine Dubois, Thomas Farge, Mathilde Gotanègre, Claudie Bosc, Estelle Saland, Marie-Laure Nicolau-Travers, Marie Sabatier, Nizar Serhan, Ambrine Sahal, Emeline Boet, Sarah Mouche, Quentin Heydt, Nesrine Aroua, Lucille Stuani, Tony Kaoma, Linus Angenendt, Jan-Henrik Mikesch, Christoph Schliemann, François Vergez, Jérôme Tamburini, Christian Récher and Jean-Emmanuel Sarry ()
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Clément Larrue: Université de Toulouse 3 Paul Sabatier
Nathan Guiraud: Université de Toulouse 3 Paul Sabatier
Pierre-Luc Mouchel: Université de Toulouse 3 Paul Sabatier
Marine Dubois: Université de Toulouse 3 Paul Sabatier
Thomas Farge: Université de Toulouse 3 Paul Sabatier
Mathilde Gotanègre: Université de Toulouse 3 Paul Sabatier
Claudie Bosc: Université de Toulouse 3 Paul Sabatier
Estelle Saland: Université de Toulouse 3 Paul Sabatier
Marie-Laure Nicolau-Travers: Université de Toulouse 3 Paul Sabatier
Marie Sabatier: Université de Toulouse 3 Paul Sabatier
Nizar Serhan: Université de Toulouse 3 Paul Sabatier
Ambrine Sahal: Université de Toulouse 3 Paul Sabatier
Emeline Boet: Université de Toulouse 3 Paul Sabatier
Sarah Mouche: Geneva University Hospitals, University of Geneva
Quentin Heydt: Université de Toulouse 3 Paul Sabatier
Nesrine Aroua: Université de Toulouse 3 Paul Sabatier
Lucille Stuani: Université de Toulouse 3 Paul Sabatier
Tony Kaoma: Luxembourg Institute of Health
Linus Angenendt: University Hospital Münster
Jan-Henrik Mikesch: University Hospital Münster
Christoph Schliemann: University Hospital Münster
François Vergez: Université de Toulouse 3 Paul Sabatier
Jérôme Tamburini: Geneva University Hospitals, University of Geneva
Christian Récher: Université de Toulouse 3 Paul Sabatier
Jean-Emmanuel Sarry: Université de Toulouse 3 Paul Sabatier

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Drug tolerant/resistant leukemic stem cell (LSC) subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these relapse-initiating cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncover that calcitonin receptor-like receptor (CALCRL) is expressed in RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM), and not CGRP, correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency, and sensitizes to cytarabine in patient-derived xenograft models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA repair, and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20717-9

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DOI: 10.1038/s41467-020-20717-9

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