Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells
Abstract
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 Statement
The authors have declared no competing interest.
Footnotes
↵9 Lead Contact
Subject Area
- Biochemistry (11753)
- Bioengineering (8754)
- Bioinformatics (29205)
- Biophysics (14975)
- Cancer Biology (12102)
- Cell Biology (17414)
- Clinical Trials (138)
- Developmental Biology (9423)
- Ecology (14185)
- Epidemiology (2067)
- Evolutionary Biology (18309)
- Genetics (12246)
- Genomics (16805)
- Immunology (11870)
- Microbiology (28098)
- Molecular Biology (11598)
- Neuroscience (60979)
- Paleontology (452)
- Pathology (1871)
- Pharmacology and Toxicology (3238)
- Physiology (4960)
- Plant Biology (10427)
- Synthetic Biology (2886)
- Systems Biology (7341)
- Zoology (1651)