Distinct and targetable role of calcium-sensing receptor in leukaemia

Raquel S. Pereira, Rahul Kumar, Alessia Cais, Lara Paulini, Alisa Kahler, Jimena Bravo, Valentina R. Minciacchi, Theresa Krack, Eric Kowarz, Costanza Zanetti, Parimala Sonika Godavarthy, Fabian Hoeller, Pablo Llavona, Tabea Stark, Georg Tascher, Daniel Nowak, Eshwar Meduri, Brian J. P. Huntly, Christian Münch, Francesco Pampaloni, Rolf Marschalek and Daniela S. Krause ()
Additional contact information
Raquel S. Pereira: Institute for Tumor Biology and Experimental Therapy
Rahul Kumar: Institute for Tumor Biology and Experimental Therapy
Alessia Cais: Hopp Children’s Cancer Center Heidelberg (KiTZ) and German Cancer Research Center (DKFZ)
Lara Paulini: Institute for Tumor Biology and Experimental Therapy
Alisa Kahler: Institute for Tumor Biology and Experimental Therapy
Jimena Bravo: Institute for Tumor Biology and Experimental Therapy
Valentina R. Minciacchi: Institute for Tumor Biology and Experimental Therapy
Theresa Krack: Institute for Tumor Biology and Experimental Therapy
Eric Kowarz: Goethe University
Costanza Zanetti: University Medical Center, Johannes Gutenberg University Mainz
Parimala Sonika Godavarthy: Institute for Tumor Biology and Experimental Therapy
Fabian Hoeller: Institute for Tumor Biology and Experimental Therapy
Pablo Llavona: Institute of Molecular Biology gGmbH (IMB)
Tabea Stark: Goethe University
Georg Tascher: Goethe University
Daniel Nowak: Heidelberg University
Eshwar Meduri: University of Cambridge
Brian J. P. Huntly: University of Cambridge
Christian Münch: Goethe University
Francesco Pampaloni: Goethe University
Rolf Marschalek: Goethe University
Daniela S. Krause: Institute for Tumor Biology and Experimental Therapy

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41770-0

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