Nature Communications (Oct 2023)

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,
  • Daniela S. Krause

DOI
https://doi.org/10.1038/s41467-023-41770-0
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 19

Abstract

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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.