RT Journal Article
SR Electronic
T1 Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.17.253542
DO 10.1101/2020.08.17.253542
A1 Clément Larrue
A1 Nathan Guiraud
A1 Pierre-Luc Mouchel
A1 Marine Dubois
A1 Thomas Farge
A1 Mathilde Gotanègre
A1 Claudie Bosc
A1 Estelle Saland
A1 Marie-Laure Nicolau-Travers
A1 Marie Sabatier
A1 Nizar Serhan
A1 Ambrine Sahal
A1 Emeline Boet
A1 Sarah Mouche
A1 Quentin Heydt
A1 Nesrine Aroua
A1 Lucille Stuani
A1 Tony Kaoma
A1 Linus Angenendt
A1 Jan-Henrik Mikesch
A1 Christoph Schliemann
A1 François Vergez
A1 Jérôme Tamburini
A1 Christian Récher
A1 Jean-Emmanuel Sarry
YR 2020
UL http://biorxiv.org/content/early/2020/08/17/2020.08.17.253542.abstract
AB 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.