TY  - JOUR
AU  - Pereira, Raquel S
AU  - Kumar, Rahul
AU  - Cais, Alessia
AU  - Paulini, Lara
AU  - Kahler, Alisa
AU  - Bravo, Jimena
AU  - Minciacchi, Valentina R
AU  - Krack, Theresa
AU  - Kowarz, Eric
AU  - Zanetti, Costanza
AU  - Godavarthy, Parimala Sonika
AU  - Hoeller, Fabian
AU  - Llavona, Pablo
AU  - Stark, Tabea
AU  - Tascher, Georg
AU  - Nowak, Daniel
AU  - Meduri, Eshwar
AU  - Huntly, Brian J P
AU  - Münch, Christian
AU  - Pampaloni, Francesco
AU  - Marschalek, Rolf
AU  - Krause, Daniela S
TI  - Distinct and targetable role of calcium-sensing receptor in leukaemia.
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2023-02023
SP  - 6242
PY  - 2023
AB  - Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa2+] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa2+] and response to [eCa2+] differ between leukaemias. CaSR influences the location of MLL-AF9+ acute myeloid leukaemia (AML) cells within this niche and differentially impacts MLL-AF9+ AML versus BCR-ABL1+ leukaemias. Deficiency of CaSR reduces AML leukaemic stem cells (LSC) 6.5-fold. CaSR interacts with filamin A, a crosslinker of actin filaments, affects stemness-associated factors and modulates pERK, β-catenin and c-MYC signaling and intracellular levels of [Ca2+] in MLL-AF9+ AML cells. Combination treatment of cytarabine plus CaSR-inhibition in various models may be superior to cytarabine alone. Our studies suggest CaSR to be a differential and targetable factor in leukaemia progression influencing self-renewal of AML LSC via [eCa2+] cues from the BMM.
LB  - PUB:(DE-HGF)16
C6  - pmid:37802982
C2  - pmc:PMC10558580
DO  - DOI:10.1038/s41467-023-41770-0
UR  - https://inrepo02.dkfz.de/record/284603
ER  -