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

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; Ambrine Sahal; Emeline Boet; Sarah Mouche; Quentin Heydt; Nesrine Aroua; Lucille Stuani; Tony Kaoma; Linus Angenendt; Jan Henrik Mikesch; Christoph Schliemann; François Vergez; Jérôme Tamburini; Christian Récher; Jean Emmanuel Sarry

doi:10.1038/s41467-020-20717-9

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

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
, Ambrine Sahal
, Emeline Boet
, Sarah Mouche
, Quentin Heydt
, Nesrine Aroua
, Lucille Stuani
, Tony Kaoma
, Linus Angenendt
, Jan Henrik Mikesch

Christoph Schliemann, François Vergez, Jérôme Tamburini, Christian Récher, Jean Emmanuel Sarry^*

^*Corresponding author for this work

Luxembourg Institute of Health

Research output: Contribution to journal › Article › Research › peer-review

54 Citations (Scopus)

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.

Original language	English
Article number	422
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20717-9
Publication status	Published - 18 Jan 2021

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Larrue, C., Guiraud, N., Mouchel, P. L., Dubois, M., Farge, T., Gotanègre, M., Bosc, C., Saland, E., Nicolau-Travers, M. L., Sabatier, M., Serhan, N., Sahal, A., Boet, E., Mouche, S., Heydt, Q., Aroua, N., Stuani, L., Kaoma, T., Angenendt, L., ... Sarry, J. E. (2021). Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells. Nature Communications, 12(1), Article 422. https://doi.org/10.1038/s41467-020-20717-9

@article{01d3f0567fc543d1835a3b9df2fdc95e,

title = "Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells",

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.",

author = "Cl{\'e}ment Larrue and Nathan Guiraud and Mouchel, \{Pierre Luc\} and Marine Dubois and Thomas Farge and Mathilde Gotan{\`e}gre and Claudie Bosc and Estelle Saland and Nicolau-Travers, \{Marie Laure\} and Marie Sabatier and Nizar Serhan and Ambrine Sahal and Emeline Boet and Sarah Mouche and Quentin Heydt and Nesrine Aroua and Lucille Stuani and Tony Kaoma and Linus Angenendt and Mikesch, \{Jan Henrik\} and Christoph Schliemann and Fran{\c c}ois Vergez and J{\'e}r{\^o}me Tamburini and Christian R{\'e}cher and Sarry, \{Jean Emmanuel\}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jan,

day = "18",

doi = "10.1038/s41467-020-20717-9",

language = "English",

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Larrue, C, Guiraud, N, Mouchel, PL, Dubois, M, Farge, T, Gotanègre, M, Bosc, C, Saland, E, Nicolau-Travers, ML, Sabatier, M, Serhan, N, Sahal, A, Boet, E, Mouche, S, Heydt, Q, Aroua, N, Stuani, L, Kaoma, T, Angenendt, L, Mikesch, JH, Schliemann, C, Vergez, F, Tamburini, J, Récher, C & Sarry, JE 2021, 'Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells', Nature Communications, vol. 12, no. 1, 422. https://doi.org/10.1038/s41467-020-20717-9

TY - JOUR

T1 - Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells

AU - Larrue, Clément

AU - Guiraud, Nathan

AU - Mouchel, Pierre Luc

AU - Dubois, Marine

AU - Farge, Thomas

AU - Gotanègre, Mathilde

AU - Bosc, Claudie

AU - Saland, Estelle

AU - Nicolau-Travers, Marie Laure

AU - Sabatier, Marie

AU - Serhan, Nizar

AU - Sahal, Ambrine

AU - Boet, Emeline

AU - Mouche, Sarah

AU - Heydt, Quentin

AU - Aroua, Nesrine

AU - Stuani, Lucille

AU - Kaoma, Tony

AU - Angenendt, Linus

AU - Mikesch, Jan Henrik

AU - Schliemann, Christoph

AU - Vergez, François

AU - Tamburini, Jérôme

AU - Récher, Christian

AU - Sarry, Jean Emmanuel

PY - 2021/1/18

Y1 - 2021/1/18

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85100040131

UR - https://www.ncbi.nlm.nih.gov/pubmed/33462236

U2 - 10.1038/s41467-020-20717-9

DO - 10.1038/s41467-020-20717-9

M3 - Article

C2 - 33462236

AN - SCOPUS:85100040131

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 422

ER -

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

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