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

• Main Authors: Tobias Gluexam, Alexander M. Grandits, Angela Schlerka, Chi Huu Nguyen, Julia Etzler, Thomas Finkes, Michael Fuchs, Christoph Scheid, Gerwin Heller, Hubert Hackl, Nathalie Harrer, Heinz Sill, Elisabeth Koller, Dagmar Stoiber, Wolfgang Sommergruber, Rotraud Wieser
• Format: Article
• Language: English
• Published: MDPI AG 2019-11-01
• Series: International Journal of Molecular Sciences
• Subjects: calcrl; cgrp; aml; relapse; chemotherapy resistance; leukemic stem cells; olcegepant
• Online Access: https://www.mdpi.com/1422-0067/20/23/5826

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 <i>CALCRL</i> 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, <i>in silico</i> analyses, human AML cell lines, primary patient samples, and a C57BL/6-based mouse model of AML are used. We find that <i>CALCRL</i> 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.