Distinct and targetable role of calcium-sensing receptor in leukaemia
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 be...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
06 October 2023
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| In: |
Nature Communications
Year: 2023, Jahrgang: 14, Pages: 1-19 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-023-41770-0 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-023-41770-0 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-023-41770-0 
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| Verfasserangaben: | 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 & Daniela S. Krause |
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| 520 | |a 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. | ||
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