Calcium-dependent signalling in B-cell lymphomas

Abstract

Induced waves of calcium fluxes initiate multiple signalling pathways that play an important role in the differentiation and maturation of B-cells. Finely tuned transient Ca+2 fluxes from the endoplasmic reticulum in response to B-cell receptor (BCR) or chemokine receptor activation are followed by more sustained calcium influxes from the extracellular environment and contribute to the mechanisms responsible for the proliferation of B-cells, their migration within lymphoid organs and their differentiation. Dysregulation of these well-balanced mechanisms in B-cell lymphomas results in uncontrolled cell proliferation and resistance to apoptosis. Consequently, several cytotoxic drugs (and anti-proliferative compounds) used in standard chemotherapy regimens for the treatment of people with lymphoma target calcium-dependent pathways. Furthermore, ~10% of lymphoma associated mutations are found in genes with functions in calcium-dependent signalling, including those affecting B-cell receptor signalling pathways. In this review, we provide an overview of the Ca2+-dependent signalling network and outline the contribution of its key components to B cell lymphomagenesis. We also consider how the oncogenic Epstein-Barr virus, which is causally linked to the pathogenesis of a number of B-cell lymphomas, can modify Ca2+-dependent signalling.

Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling

“…Collectively, these findings demonstrate that PLC promotes survival signaling in B-ALL cells by regulating cell cycle progression and division and beyond that, a complex program of gene expression. Dex exposure triggers Ca 2+ signaling through the PLCγ2 pathway in B-ALL cells Given the importance of PLCγ2 for B cell function 10,15,16,18,19 and intracellular Ca 2+ signals for B-ALL cell resistance to Dex 8 , we investigated the role of PLCγ2 in Dex-mediated Ca 2+ signaling in B-ALL. To optically measure cytosolic Ca 2+ shifts, we used single-cell Ca 2+ imaging by fluorescence microscopy following stimulation of B-ALL cells with Dex (Fig.…”

“…Mutations in molecules controlling Ca 2+ homeostasis have been associated with an increased incidence of tumors [12][13][14] , but many key elements of that association are not fully understood. In B cells, initial Ca 2+ signals are generated by the actions of cell surface receptors (CSR) through (i) engagement of the B cell receptor (BCR) by antigens or (ii) G-proteincoupled chemokine receptors [15][16][17] . Either way, CSR activate the phospholipase C (PLC) signaling pathway and the production of inositol 1, 4, 5-trisphosphate (IP 3 ) resulting in the release of Ca 2+ from the endoplasmic reticulum (ER) into the cytoplasm via IP 3 receptors (IP 3 R) and diacylglycerol (DAG)-mediated activation of protein kinase C (PKC) 15 .…”

“…In B cells, initial Ca 2+ signals are generated by the actions of cell surface receptors (CSR) through (i) engagement of the B cell receptor (BCR) by antigens or (ii) G-proteincoupled chemokine receptors [15][16][17] . Either way, CSR activate the phospholipase C (PLC) signaling pathway and the production of inositol 1, 4, 5-trisphosphate (IP 3 ) resulting in the release of Ca 2+ from the endoplasmic reticulum (ER) into the cytoplasm via IP 3 receptors (IP 3 R) and diacylglycerol (DAG)-mediated activation of protein kinase C (PKC) 15 . This pathway plays a crucial role in many biological functions (e.g., proliferation and survival) by activating the transcription of various target genes 18 .…”

An Update on Protein Kinases as Therapeutic Targets—Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases

“…PKCβ also modulates angiogenesis via vascular endothelial growth factor (VEGF), which enhances tumor progression [183] and is associated with worse prognoses in NHL [184]. PKCβ was especially overexpressed in treatment-refractory diffuse large B-cell lymphoma (DLBCL), an aggressive, and the most common, type of NHL [185,186].…”

Familial non‐Hodgkin lymphoma with inborn error of immunity due to ORAI1 defect

“…Also, rituximab, which targets CD20, induces both transient and sustained (ORAI1-dependent) influx of Ca 2+ to the cytoplasm and activation of Ca-dependent signaling pathways linked to the antibody-induced cell death. 15 In a retrospective study of 497 childhood NHL patients and in the Surveillance, Epidemiology, and End Results (SEER) registry, which included 1757 patients with primary BL, 3.2%-4.55% developed a second malignant neoplasm (SMN), which included solid tumors and acute myeloid leukemia (AML). 16 In the Berlin-Frankfurt-Muenster (BFM) cohort of childhood NHL, carcinomas were the most frequent SMNs after NHL, followed by AML and other lymphoid malignancies.…”