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

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

Research output: Journal article (peer-reviewed)Journal article

16 Citations (Scopus)

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.

Original languageEnglish
Article number5826
JournalInternational Journal of Molecular Sciences
Volume20
Issue number23
DOIs
Publication statusPublished - 1 Dec 2019

Keywords

  • Animals
  • Antibiotics, Antineoplastic/pharmacology
  • Apoptosis/drug effects
  • Calcitonin Gene-Related Peptide/metabolism
  • Calcitonin Receptor-Like Protein/antagonists & inhibitors
  • Cell Line, Tumor
  • Daunorubicin/pharmacology
  • Dipeptides/pharmacology
  • Drug Resistance, Neoplasm
  • Female
  • Hematopoietic Stem Cells/metabolism
  • Humans
  • Leukemia, Myeloid, Acute/drug therapy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Neoplastic Stem Cells/metabolism
  • Piperazines
  • Quinazolines/pharmacology
  • Signal Transduction

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