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Distinct and targetable role of calcium-sensing receptor in leukaemia

Author

Listed:
  • 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
    Goethe University
    Goethe-University
    German Cancer Research Center (DKFZ))

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.

Suggested Citation

  • 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 & Fa, 2023. "Distinct and targetable role of calcium-sensing receptor in leukaemia," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41770-0
    DOI: 10.1038/s41467-023-41770-0
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    References listed on IDEAS

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