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 MikeschChristoph Schliemann, François Vergez, Jérôme Tamburini, Christian Récher, Jean Emmanuel Sarry*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Article number422
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 18 Jan 2021

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