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CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
Comprehensive Cancer Center, Spitalgasse 23, 1090 Vienna, Austria
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innrain 80, 6020 Innsbruck, Austria
Department for Cancer Research, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, 8036 Graz, Austria
Third Medical Department, Hanusch Hospital, Heinrich Collinstrasse 30, 1140 Vienna, Austria
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringer Strasse 13A, 1090 Vienna, Austria
Division Pharmacology, Department Pharmacology, Physiology and Microbiology, Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Straße 30, 3500 Krems, Austria
Department of Biotechnology, University of Applied Sciences, Helmut-Qualtinger-Gasse 2, 1030 Vienna, Austria
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(23), 5826;
Received: 27 September 2019 / Revised: 15 November 2019 / Accepted: 18 November 2019 / Published: 20 November 2019
(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)
The neuropeptide CGRP, acting through the G-protein coupled receptor CALCRL and its coreceptor RAMP1, plays a key role in migraines, which has led to the clinical development of several inhibitory compounds. Recently, high CALCRL expression has been shown to be associated with a poor prognosis in acute myeloid leukemia (AML). We investigate, therefore, the functional role of the CGRP-CALCRL axis in AML. To this end, in silico analyses, human AML cell lines, primary patient samples, and a C57BL/6-based mouse model of AML are used. We find that CALCRL is up-regulated at relapse of AML, in leukemic stem cells (LSCs) versus bulk leukemic cells, and in LSCs versus normal hematopoietic stem cells. CGRP protects receptor-positive AML cell lines and primary AML samples from apoptosis induced by cytostatic drugs used in AML therapy, and this effect is inhibited by specific antagonists. Furthermore, the CGRP antagonist olcegepant increases differentiation and reduces the leukemic burden as well as key stem cell properties in a mouse model of AML. These data provide a basis for further investigations into a possible role of CGRP-CALCRL inhibition in the therapy of AML. View Full-Text
Keywords: CALCRL; CGRP; AML; relapse; chemotherapy resistance; leukemic stem cells; olcegepant CALCRL; CGRP; AML; relapse; chemotherapy resistance; leukemic stem cells; olcegepant
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Gluexam, T.; Grandits, A.M.; Schlerka, A.; Nguyen, C.H.; Etzler, J.; Finkes, T.; Fuchs, M.; Scheid, C.; Heller, G.; Hackl, H.; Harrer, N.; Sill, H.; Koller, E.; Stoiber, D.; Sommergruber, W.; Wieser, R. CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia. Int. J. Mol. Sci. 2019, 20, 5826.

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