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Distinct and targetable role of calcium-sensing receptor in leukaemia.

Published version
Peer-reviewed

Repository DOI


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Authors

Kumar, Rahul 
Cais, Alessia 
Paulini, Lara 
Kahler, Alisa 

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.

Description

Acknowledgements: This work was supported by grant 70113903 to D.S.K. from the Deutsche Krebshilfe. We thank the Quantitative Proteomics Unit (Institute of Biochemistry II, Goethe University Frankfurt) for support on LC-MS instrumentation and the DFG for funding the Orbitrap Lumos LC-MS system used in this study (FuG 403765277). D.N. is an endowed professor of the German José-Carreras-Foundation (DJCLSH03/01).

Keywords

Humans, Receptors, Calcium-Sensing, Proto-Oncogene Proteins c-myc, Calcium, Oncogene Proteins, Fusion, Signal Transduction, Leukemia, Myeloid, Acute, Cytarabine, Tumor Microenvironment

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

14

Publisher

Springer Science and Business Media LLC
Sponsorship
Deutsche Krebshilfe (German Cancer Aid) (70113903)