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- W4387399259 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." @default.
- W4387399259 created "2023-10-07" @default.
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- W4387399259 date "2023-10-06" @default.
- W4387399259 modified "2023-10-11" @default.
- W4387399259 title "Distinct and targetable role of calcium-sensing receptor in leukaemia" @default.
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- W4387399259 doi "https://doi.org/10.1038/s41467-023-41770-0" @default.
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- W4387399259 hasPublicationYear "2023" @default.
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