Gluexam, Tobias, Grandits, Alexander M., Schlerka, Angela, Etzler, Julia, Finkes, Thomas, Fuchs, Michael, Scheid, Christoph, Heller, Gerwin, Hackl, Hubert ORCID: 0000-0003-4055-3841, Harrer, Nathalie, Sill, Heinz ORCID: 0000-0003-0993-4371, Koller, Elisabeth ORCID: 0000-0002-9912-0461, Stoiber, Dagmar, Sommergruber, Wolfgang and Wieser, Rotraud ORCID: 0000-0003-4384-6658 (2019). CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia. Int. J. Mol. Sci., 20 (23). BASEL: MDPI. ISSN 1422-0067

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gluexam, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grandits, Alexander M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlerka, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Etzler, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finkes, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuchs, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheid, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heller, GerwinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hackl, HubertUNSPECIFIEDorcid.org/0000-0003-4055-3841UNSPECIFIED
Harrer, NathalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sill, HeinzUNSPECIFIEDorcid.org/0000-0003-0993-4371UNSPECIFIED
Koller, ElisabethUNSPECIFIEDorcid.org/0000-0002-9912-0461UNSPECIFIED
Stoiber, DagmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sommergruber, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wieser, RotraudUNSPECIFIEDorcid.org/0000-0003-4384-6658UNSPECIFIED
URN: urn:nbn:de:hbz:38-125680
DOI: 10.3390/ijms20235826
Journal or Publication Title: Int. J. Mol. Sci.
Volume: 20
Number: 23
Date: 2019
Publisher: MDPI
Place of Publication: BASEL
ISSN: 1422-0067
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE-RELATED PEPTIDE; EXPRESSION SIGNATURE; APOPTOSIS; RECEPTOR; PREDICTION; MUTATIONS; INDUCTION; PROGNOSIS; SUBTYPES; RELAPSEMultiple languages
Biochemistry & Molecular Biology; Chemistry, MultidisciplinaryMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12568

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