TY - JOUR TI - Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells AU - Larrue, Clément AU - Guiraud, Nathan AU - Mouchel, Pierre-Luc AU - Dubois, Marine AU - Farge, Thomas AU - Gotanègre, Mathilde AU - Bosc, Claudie AU - Saland, Estelle AU - Nicolau-Travers, Marie-Laure AU - Sabatier, Marie AU - Serhan, Nizar AU - Sahal, Ambrine AU - Boet, Emeline AU - Mouche, Sarah AU - Heydt, Quentin AU - Aroua, Nesrine AU - Stuani, Lucille AU - Kaoma, Tony AU - Angenendt, Linus AU - Mikesch, Jan-Henrik AU - Schliemann, Christoph AU - Vergez, François AU - Tamburini, Jérôme AU - Récher, Christian AU - Sarry, Jean-Emmanuel T2 - Nature Communications AB - 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. DA - 2021/01/18/ PY - 2021 DO - 10.1038/s41467-020-20717-9 DP - www.nature.com VL - 12 IS - 1 SP - 422 LA - en SN - 2041-1723 UR - https://www.nature.com/articles/s41467-020-20717-9 Y2 - 2021/01/18/20:19:51 ER -