%0 Journal Article
%A Pereira, Raquel S
%A Kumar, Rahul
%A Cais, Alessia
%A Paulini, Lara
%A Kahler, Alisa
%A Bravo, Jimena
%A Minciacchi, Valentina R
%A Krack, Theresa
%A Kowarz, Eric
%A Zanetti, Costanza
%A Godavarthy, Parimala Sonika
%A Hoeller, Fabian
%A Llavona, Pablo
%A Stark, Tabea
%A Tascher, Georg
%A Nowak, Daniel
%A Meduri, Eshwar
%A Huntly, Brian J P
%A Münch, Christian
%A Pampaloni, Francesco
%A Marschalek, Rolf
%A Krause, Daniela S
%T Distinct and targetable role of calcium-sensing receptor in leukaemia.
%J Nature Communications
%V 14
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DKFZ-2023-02023
%P 6242
%D 2023
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37802982
%2 pmc:PMC10558580
%R 10.1038/s41467-023-41770-0
%U https://inrepo02.dkfz.de/record/284603