TY - JOUR T1 - Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells JF - bioRxiv DO - 10.1101/2020.08.17.253542 SP - 2020.08.17.253542 AU - Clément Larrue AU - Nathan Guiraud AU - Pierre-Luc Mouchel AU - Marine Dubois AU - Thomas Farge AU - Mathilde Gotanègre AU - Claudie Bosc AU - Estelle Saland AU - Marie-Laure Nicolau-Travers AU - Marie Sabatier AU - Nizar Serhan AU - Ambrine Sahal AU - Emeline Boet AU - Sarah Mouche AU - Quentin Heydt AU - Nesrine Aroua AU - Lucille Stuani AU - Tony Kaoma AU - Linus Angenendt AU - Jan-Henrik Mikesch AU - Christoph Schliemann AU - François Vergez AU - Jérôme Tamburini AU - Christian Récher AU - Jean-Emmanuel Sarry Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/08/17/2020.08.17.253542.abstract N2 - Drug tolerant leukemic cell 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 uncovered that the G-protein coupled receptor CALCRL is expressed in leukemic stem cells (LSCs) and 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 (PDX) 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.Competing Interest StatementThe authors have declared no competing interest. ER -