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Pereira, Raquel S.; Kumar, Rahul; Cais, Alessia; Paulini, Lara; Kahler, Alisa; Bravo, Jimena; Minciacchi, Valentina R.; Krack, Theresa; Kowarz, Eric; Zanetti, Costanza; Godavarthy, Parimala Sonika; Hoeller, Fabian; Llavona, Pablo; Stark, Tabea; Tascher, Georg; Nowak, Daniel; Meduri, Eshwar; Huntly, Brian J. P.; Münch, Christian; Pampaloni, Francesco; Marschalek, Rolf; Krause, Daniela S.

Distinct and targetable role of calcium-sensing receptor in leukaemia

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  • Medientyp: E-Artikel
  • Titel: Distinct and targetable role of calcium-sensing receptor in leukaemia
  • Beteiligte: Pereira, Raquel S.; Kumar, Rahul; Cais, Alessia; Paulini, Lara; Kahler, Alisa; Bravo, Jimena; Minciacchi, Valentina R.; Krack, Theresa; Kowarz, Eric; Zanetti, Costanza; Godavarthy, Parimala Sonika; Hoeller, Fabian; Llavona, Pablo; Stark, Tabea; Tascher, Georg; Nowak, Daniel; Meduri, Eshwar; Huntly, Brian J. P.; Münch, Christian; Pampaloni, Francesco; Marschalek, Rolf; Krause, Daniela S.
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-023-41770-0
  • ISSN: 2041-1723
  • Schlagwörter: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa<jats:sup>2+</jats:sup>] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa<jats:sup>2+</jats:sup>] and response to [eCa<jats:sup>2+</jats:sup>] differ between leukaemias. CaSR influences the location of MLL-AF9<jats:sup>+</jats:sup> acute myeloid leukaemia (AML) cells within this niche and differentially impacts MLL-AF9<jats:sup>+</jats:sup> AML versus BCR-ABL1<jats:sup>+</jats:sup> 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, <jats:italic>β</jats:italic>-catenin and c-MYC signaling and intracellular levels of [Ca<jats:sup>2+</jats:sup>] in MLL-AF9<jats:sup>+</jats:sup> 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 [eCa<jats:sup>2+</jats:sup>] cues from the BMM.</jats:p>
  • Zugangsstatus: Freier Zugang