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

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Larrue, Clément | Guiraud, Nathan | Mouchel, Pierre-Luc | Dubois, Marine | Farge, Thomas | Gotanègre, Mathilde | Bosc, Claudie | Saland, Estelle | Nicolau-Travers, Marie-Laure | Sabatier, Marie | Serhan, Nizar | Sahal, Ambrine | Boet, Emeline | Mouche, Sarah | Heydt, Quentin | Aroua, Nesrine | Stuani, Lucille | Kaoma, Tony | Angenendt, Linus | Mikesch, Jan-Henrik | Schliemann, Christoph | Vergez, François | Tamburini, Jérôme | Récher, Christian | Sarry, Jean-Emmanuel

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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