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

Int J Mol Sci 2019 Nov 20;20(23). Epub 2019 Nov 20.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

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

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20235826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928760PMC
November 2019
4 Reads

Publication Analysis

Top Keywords

aml
10
model aml
8
acute myeloid
8
cell properties
8
stem cell
8
myeloid leukemia
8
lscs versus
8
cells lscs
8
stem cells
8
lines primary
8
mouse model
8
aml cell
8
cell lines
8
role cgrp-calcrl
8
functional role
4
leukemic stem
4
versus bulk
4
cgrp-calcrl axis
4
leukemic cells
4
hematopoietic stem
4

References

(Supplied by CrossRef)

Similar Publications