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

Author

Listed:
  • Clément Larrue

    (Université de Toulouse 3 Paul Sabatier
    Geneva University Hospitals, University of Geneva)

  • Nathan Guiraud

    (Université de Toulouse 3 Paul Sabatier)

  • Pierre-Luc Mouchel

    (Université de Toulouse 3 Paul Sabatier
    Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse)

  • Marine Dubois

    (Université de Toulouse 3 Paul Sabatier)

  • Thomas Farge

    (Université de Toulouse 3 Paul Sabatier)

  • Mathilde Gotanègre

    (Université de Toulouse 3 Paul Sabatier)

  • Claudie Bosc

    (Université de Toulouse 3 Paul Sabatier)

  • Estelle Saland

    (Université de Toulouse 3 Paul Sabatier)

  • Marie-Laure Nicolau-Travers

    (Université de Toulouse 3 Paul Sabatier
    Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse)

  • Marie Sabatier

    (Université de Toulouse 3 Paul Sabatier)

  • Nizar Serhan

    (Université de Toulouse 3 Paul Sabatier)

  • Ambrine Sahal

    (Université de Toulouse 3 Paul Sabatier)

  • Emeline Boet

    (Université de Toulouse 3 Paul Sabatier)

  • Sarah Mouche

    (Geneva University Hospitals, University of Geneva)

  • Quentin Heydt

    (Université de Toulouse 3 Paul Sabatier)

  • Nesrine Aroua

    (Université de Toulouse 3 Paul Sabatier)

  • Lucille Stuani

    (Université de Toulouse 3 Paul Sabatier)

  • Tony Kaoma

    (Luxembourg Institute of Health)

  • Linus Angenendt

    (University Hospital Münster)

  • Jan-Henrik Mikesch

    (University Hospital Münster)

  • Christoph Schliemann

    (University Hospital Münster)

  • François Vergez

    (Université de Toulouse 3 Paul Sabatier
    Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse)

  • Jérôme Tamburini

    (Geneva University Hospitals, University of Geneva
    Reproduction et Cancer
    Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité)

  • Christian Récher

    (Université de Toulouse 3 Paul Sabatier
    Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse)

  • Jean-Emmanuel Sarry

    (Université de Toulouse 3 Paul Sabatier)

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.

Suggested Citation

  • 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 &, 2021. "Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20717-9
    DOI: 10.1038/s41467-020-20717-9
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