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.