Next Article in Journal
In Silico Approach for the Definition of radiomiRNomic Signatures for Breast Cancer Differential Diagnosis
Next Article in Special Issue
The Role of Reactive Oxygen Species in Acute Myeloid Leukaemia
Previous Article in Journal
Molecular Interactions between Pathogens and the Circadian Clock
Previous Article in Special Issue
RAF Kinase Inhibitor Protein in Myeloid Leukemogenesis
Open AccessArticle

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

1
Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
2
Comprehensive Cancer Center, Spitalgasse 23, 1090 Vienna, Austria
3
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany
4
Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innrain 80, 6020 Innsbruck, Austria
5
Department for Cancer Research, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria
6
Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, 8036 Graz, Austria
7
Third Medical Department, Hanusch Hospital, Heinrich Collinstrasse 30, 1140 Vienna, Austria
8
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringer Strasse 13A, 1090 Vienna, Austria
9
Division Pharmacology, Department Pharmacology, Physiology and Microbiology, Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Straße 30, 3500 Krems, Austria
10
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; https://doi.org/10.3390/ijms20235826
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
Show Figures

Figure 1

MDPI and ACS Style

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.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop