TY - JOUR
T1 - CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia
AU - Gluexam, Tobias
AU - Grandits, Alexander M
AU - Schlerka, Angela
AU - Nguyen, Chi Huu
AU - Etzler, Julia
AU - Finkes, Thomas
AU - Fuchs, Michael
AU - Scheid, Christoph
AU - Heller, Gerwin
AU - Hackl, Hubert
AU - Harrer, Nathalie
AU - Sill, Heinz
AU - Koller, Elisabeth
AU - Stoiber, Dagmar
AU - Sommergruber, Wolfgang
AU - Wieser, Rotraud
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Animals
KW - Antibiotics, Antineoplastic/pharmacology
KW - Apoptosis/drug effects
KW - Calcitonin Gene-Related Peptide/metabolism
KW - Calcitonin Receptor-Like Protein/antagonists & inhibitors
KW - Cell Line, Tumor
KW - Daunorubicin/pharmacology
KW - Dipeptides/pharmacology
KW - Drug Resistance, Neoplasm
KW - Female
KW - Hematopoietic Stem Cells/metabolism
KW - Humans
KW - Leukemia, Myeloid, Acute/drug therapy
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Middle Aged
KW - Neoplastic Stem Cells/metabolism
KW - Piperazines
KW - Quinazolines/pharmacology
KW - Signal Transduction
UR - http://www.scopus.com/inward/record.url?scp=85075312474&partnerID=8YFLogxK
U2 - 10.3390/ijms20235826
DO - 10.3390/ijms20235826
M3 - Journal article
C2 - 31756985
SN - 1661-6596
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 23
M1 - 5826
ER -