Calcium metabolism | EPFL Graph Search

Calcium metabolism is the movement and regulation of calcium ions (Ca2+) in (via the gut) and out (via the gut and kidneys) of the body, and between body compartments: the blood plasma, the extracellular and intracellular fluids, and bone. Bone acts as a calcium storage center for deposits and withdrawals as needed by the blood via continual bone remodeling. An important aspect of calcium metabolism is plasma calcium homeostasis, the regulation of calcium ions in the blood plasma within narrow limits. The level of the calcium in plasma is regulated by the hormones parathyroid hormone (PTH) and calcitonin. PTH is released by the chief cells of the parathyroid glands when the plasma calcium level falls below the normal range in order to raise it; calcitonin is released by the parafollicular cells of the thyroid gland when the plasma level of calcium is above the normal range in order to lower it. Calcium is the most abundant mineral in the human body. The average adult body contains in total approximately 1 kg, 99% in the skeleton in the form of calcium phosphate salts. The extracellular fluid (ECF) contains approximately 22 mmol, of which about 9 mmol is in the plasma. Approximately 10 mmol of calcium is exchanged between bone and the ECF over a period of twenty-four hours. The concentration of calcium ions inside cells (in the intracellular fluid) is more than 7,000 times lower than in the blood plasma (i.e. at

The chromatin remodeller Chd7 and the calcium ATPase Serca2 - adding new facets to the role of Notch in Hematopoiesis and T-ALL

Monique Coersmeyer

Project I: Chd7 Deficiency does not affect N1-driven T-ALL Induction and Maintenance nor impair Hematopoiesis Notch1 has been shown to be a key driver in pediatric T-cell acute lymphobastic leukemia (T-ALL). Previous work in the lab identified the chromatin-remodeling enzyme Chd7 to be highly over-expressed in aggressive versus pre-malignant disease. The aim of this project was to study if Chd7 is required during T-ALL initiation and disease maintenance as well as to characterize its role in the hematopoietic system under physiological and stress conditions. Therefore, Chd7 cKO animals were crossed with the MxCre deleter to ablate Chd7 specifically in BM progenitors. Chd7 deficiency did not induce any overt phenotype in the hematopoietic system, when studied under âsteadyâ state or stress conditions. In addition, Chd7 proved to be dispensable in the initiation and maintenance of murine and human Notch1-driven T-ALL. Therefore, we can rule out a role of Chd7 during late-stage leukemogenesis in Notch1-induced murine and human T-ALL. Project II: Serca2, a putative drug target to fight Notch1-driven T cell acute lymphoblastic leukemia, and its role in Hematopoiesis The Notch signalling pathway represents a bona fide drug target. We and Roti et al. performed a chemical compound screen and identified Cyclopiazonic acid (CPA) as potent Notch inhibitor. Biological target of this compound is the Sarco/Endoplasmic Reticulum ATPase2 (Serca2) that is involved in calcium homeostasis within the cell. Recently, it was shown that Serca2 regulates Notch1 (N1) receptor maturation and inhibition of Serca ATPases, using thapsigargin, blocks T-ALL progression in xenografts (Roti et al., 2013). The putative global effects of Serca2 inhibition on hematopoiesis have, however, not been addressed in this study. Aim of this study was to characterize the function of Serca2 in the hematopoietic system. Therefore, we crossed Serca2 cKO with MxCre to ablate Serca2 function in BM progenitors. Serca2 haploinsufficiency did not lead to any overt phenotype under physiological or competitive conditions. In contrast, Serca2ÎMxCre chimeras showed (i) impaired long-term reconstitution capacity upon transplantation, (ii) a severe reduction of total BM, splenic and thymic cellularity and (iii) an enrichment of KLS cells, the cell pool that contains HSCs. Mature lineages were highly apoptotic, while KLS were not majorly affected by apoptosis, resided predominantly in G0 phase of the cell cycle, exhibited slower cycling kinetics and were functionally impaired as they formed less and smaller colony forming units in vitro. Deregulated calcium levels can lead to an accumulation of unfolded proteins in the ER. In order to resolve ER stress, the cell activates the unfolded protein response (UPR). In case of unresolved ER stress, however, the cell undergoes apoptosis. We demonstrate that mature hematopoietic lineages up-regulate UPR-associated and pro-apoptotic genes, while KLS cells, in contrast, show unperturbed expression of these genes. In addition, we performed in vitro experiments, inhibiting Serca function in Lin- BM cells via thapsigargin (TH) treatment. TH induced severe apoptosis in the overall cell population, while KLS accumulated and were blocked in the G0 phase, closely mimicking Serca2 LOF in vivo. We therefore question the therapeutic approach of targeting Serca2 in N1-driven T-ALL due to severe side effects induced by Serca2 inactivation in the BM.

EPFL2015

The chromatin remodeller Chd7 and the calcium ATPase Serca2 - adding new facets to the role of Notch in Hematopoiesis and T-ALL

Monique Coersmeyer

EPFL2015