Journal Article

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

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

2021

Overview

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. Leukemic stem cells which are resistant to chemotherapy are proposed as relapse-initiating cells (RICs). Here, the authors show that targeting the adrenomedullin-calcitonin receptor-like receptor decreases RICs frequency improving chemotherapy response in AML preclinical models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/105 / 13/2 / 13/31 / 38 / 38/61 / 38/89 / 631/532 / 631/67/1990 / Acute myeloid leukemia / Adrenomedullin / Adrenomedullin - metabolism / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Calcitonin / Calcitonin gene-related peptide / Calcitonin Gene-Related Peptide - metabolism / Calcitonin Receptor-Like Protein - genetics / Calcitonin Receptor-Like Protein - metabolism / Cancer / Cell cycle / Cell Cycle - drug effects / Cell Cycle - genetics / Cell Line, Tumor / Chemotherapy / Cytarabine / Depletion / DNA repair / DNA Repair - drug effects / DNA Repair - genetics / Drug resistance / Drug Resistance, Neoplasm - genetics / Female / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Hematology / Human health and pathology / Humanities and Social Sciences / Humans / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - mortality / Leukemia, Myeloid, Acute - pathology / Life Sciences / Male / Mice / Mitochondrial DNA / multidisciplinary / Myeloid leukemia / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - pathology / Neoplasm Recurrence, Local - prevention & control / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - pathology / Oxidative Phosphorylation - drug effects / Pharmaceutical sciences / Pharmacology / Primary Cell Culture / Prognosis / Receptors / Science / Science (multidisciplinary) / Stem cells / Subpopulations / Therapeutic targets / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation