Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

Larrue, C.; Guiraud, N.; Mouchel, P.-L.; Dubois, M.; Farge, T.; Gotanegre, M.; Bosc, C.; Saland, E.; Travers-Nicolau, M.-L.; Sabatier, M.; Serhan, N.; Sahal, A.; Boet, E.; Mouche, S.; Heydt, Q.; Aroua, N.; Stuani, L.; Kaoma, T.; Angenendt, L.; Mikesch, J.-H.; Schliemann, C.; Vergez, F.; Tamburini, J.; Recher, C.; Sarry, J.-E.

doi:10.1101/2020.08.17.253542

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bioRxiv · 10.1101/2020.08.17.253542

Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

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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.

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Larrue, C., Guiraud, N., Mouchel, P.-L., Dubois, M., Farge, T., Gotanegre, M., Bosc, C., Saland, E., Travers-Nicolau, M.-L., Sabatier, M., Serhan, N., Sahal, A., Boet, E., Mouche, S., Heydt, Q., Aroua, N., Stuani, L., Kaoma, T., Angenendt, L., Mikesch, J.-H., Schliemann, C., Vergez, F., Tamburini, J., Recher, C., Sarry, J.-E.. 2020-08-17. Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells. https://doi.org/10.1101/2020.08.17.253542

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