Dataset Information

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

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.

SUBMITTER: Pereira RS

PROVIDER: S-EPMC10558580 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Pereira Raquel S RS Kumar Rahul R Cais Alessia A Paulini Lara L Kahler Alisa A Bravo Jimena J Minciacchi Valentina R VR Krack Theresa T Kowarz Eric E Zanetti Costanza C Godavarthy Parimala Sonika PS Hoeller Fabian F Llavona Pablo P Stark Tabea T Tascher Georg G Nowak Daniel D Meduri Eshwar E Huntly Brian J P BJP Münch Christian C Pampaloni Francesco F Marschalek Rolf R Krause Daniela S DS

Nature communications 20231006 1

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+</s ...[more]

PMID: 37802982

Similar Datasets

Project description:The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter's syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets