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

Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa ²⁺ ] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa ²⁺ ] and response to [eCa ²⁺ ] 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 [Ca ²⁺ ] 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 [eCa ²⁺ ] cues from the BMM.
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