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- Title
Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells.
- Authors
Larrue, Clément; Guiraud, Nathan; Mouchel, Pierre-Luc; Dubois, Marine; Farge, Thomas; Gotanègre, Mathilde; Bosc, Claudie; Saland, Estelle; Nicolau-Travers, Marie-Laure; Sabatier, Marie; Serhan, Nizar; Sahal, Ambrine; Boet, Emeline; Mouche, Sarah; Heydt, Quentin; Aroua, Nesrine; Stuani, Lucille; Kaoma, Tony; Angenendt, Linus; Mikesch, Jan-Henrik
- 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. 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.
- Subjects
ACUTE myeloid leukemia; CALCITONIN receptors; DRUG control; DRUG tolerance; STEM cells; SUBSTANCE abuse relapse
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-20717-9