Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential

Immanuel, Tracey; Li, Jixia; Green, Taryn N.; Bogdanova, Anna; Kalev‐Zylinska, Maggie L.

doi:10.3389/fonc.2022.1010506

Cited by 5 publications

(5 citation statements)

References 397 publications

(508 reference statements)

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“…Finally, changes in intracellular Ca 2+ homeostasis occur in myeloproliferative neoplasms and may contribute to disease pathogenesis through ER stress (Di Buduo et al, 2020;Immanuel et al, 2022;Pietra et al, 2016;Seetharam et al, 2023). Thus, our data provide further evidence for the importance of calcium signaling in megakaryopoiesis.…”

Section: Activation Of Upr Does Not Enhance Pma-induced Maturation Of...supporting

confidence: 52%

“…Ca 2+ -dependent activation of Ca 2+ /calmodulin-dependent protein kinase (CaMK) induces transcription of CREB (c-AMP response element-binding protein) to activate the genes with CRE elements, including megakaryocyte-lineage specific genes such as FLI1, HOXC6, MXD3, PRDM16, FOXB1, TBX6, HDAC11 and NPAS1 [58,59,62]. Finally, changes in intracellular Ca 2+ homeostasis occur in myeloproliferative neoplasms and may contribute to disease pathogenesis through ER stress [63][64][65][66].…”

Section: Discussionmentioning

confidence: 99%

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Megakaryocyte maturation involves activation of the adaptive unfolded protein response

Faiz

Kalev‐Zylinska

Singleton

et al. 2023

Preprint

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Endoplasmic reticulum stress triggers the unfolded protein response (UPR) to promote cell survival or apoptosis. Transient endoplasmic reticulum stress activation has been reported to trigger megakaryocyte production, and UPR activation has been reported as a feature of megakaryocytic cancers. However, the role of UPR signaling in megakaryocyte biology is not fully understood. We studied the involvement of UPR in human megakaryocytic differentiation using PMA (phorbol 12-myristate 13-acetate)-induced maturation of megakaryoblastic cell lines and thrombopoietin-induced differentiation of human peripheral blood-derived hematopoietic stem cells. Our results demonstrate that an adaptive UPR mediated by IRE1α (inositol-requiring enzyme 1α) endonuclease activity is required for megakaryocyte differentiation. Differentiation did not alter the response to the canonical endoplasmic reticulum stressors DTT or thapsigargin. However, thapsigargin, but not DTT, inhibited differentiation, consistent with the involvement of Ca2+signaling in megakaryocyte differentiation.

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Section: Activation Of Upr Does Not Enhance Pma-induced Maturation Of...supporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Megakaryocyte maturation involves activation of the adaptive unfolded protein response

Faiz

Kalev‐Zylinska

Singleton

et al. 2023

Preprint

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“…These results are in line with the here described hypersensitivity in Ca 2+ flux of SOCE in JAK2-V617F cells. This anticipates that dysregulation of SOCE contributes to altered cellular behavior and may eventually contribute to increased thrombotic propensity [ 50 , 51 ]. The latter is a clinical hallmark of MPNs and appears to be partly due to hypersensitivity in integrin activation [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Activating mutations in JAK2 and CALR differentially affect intracellular calcium flux in store operated calcium entry

Bhuria,

Franz,

Baldauf

et al. 2024

Cell Commun Signal

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Background Calcium (Ca2+) signaling regulates various vital cellular functions, including integrin activation and cell migration. Store-operated calcium entry (SOCE) via calcium release-activated calcium (CRAC) channels represents a major pathway for Ca2+ influx from the extracellular space in multiple cell types. The impact of JAK2-V617F and CALR mutations which are disease initiating in myeloproliferative neoplasms (MPN) on SOCE, calcium flux from the endoplasmic reticulum (ER) to the cytosol, and related key signaling pathways in the presence or absence of erythropoietin (EPO) or thrombopoietin (TPO) is poorly understood. Thus, this study aimed to elucidate the effects of these mutations on the aforementioned calcium dynamics, in cellular models of MPN. Methods Intracellular Ca2+ levels were measured over a time frame of 0–1080 s in Fura-2 AM labeled myeloid progenitor 32D cells expressing various mutations (JAK2-WT/EpoR, JAK2-V617F/EpoR; CALR-WT/MPL, CALR-ins5/MPL, and del52/MPL). Basal Ca2+ concentrations were assessed from 0–108 s. Subsequently, cells were stimulated with EPO/TPO in Ca2+-free Ringer solution, measuring Ca2+ levels from 109–594 s (store depletion). Then, 2 mM of Ca2+ buffer resembling physiological concentrations was added to induce SOCE, and Ca2+ levels were measured from 595–1080 s. Fura-2 AM emission ratios (F340/380) were used to quantify the integrated Ca2+ signal. Statistical significance was assessed by unpaired Student's t-test or Mann–Whitney-U-test, one-way or two-way ANOVA followed by Tukey's multiple comparison test. Results Following EPO stimulation, the area under the curve (AUC) representing SOCE significantly increased in 32D-JAK2-V617F cells compared to JAK2-WT cells. In TPO-stimulated CALR cells, we observed elevated Ca2+ levels during store depletion and SOCE in CALR-WT cells compared to CALR-ins5 and del52 cells. Notably, upon stimulation, key components of the Ca2+ signaling pathways, including PLCγ-1 and IP3R, were differentially affected in these cell lines. Hyper-activated PLCγ-1 and IP3R were observed in JAK2-V617F but not in CALR mutated cells. Inhibition of calcium regulatory mechanisms suppressed cellular growth and induced apoptosis in JAK2-V617F cells. Conclusions This report highlights the impact of JAK2 and CALR mutations on Ca2+ flux (store depletion and SOCE) in response to stimulation with EPO and TPO. The study shows that the JAK2-V617F mutation strongly alters the regulatory mechanism of EpoR/JAK2-dependent intracellular calcium balance, affecting baseline calcium levels, EPO-induced calcium entry, and PLCγ-1 signaling pathways. Our results reveal an important role of calcium flux in the homeostasis of JAK2-V617F positive cells.

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“…[ 34 , 35 ] Altered calcium signaling pathways, resulting from mutations or changes in expression of calcium channels and effectors, can impact all facets of cancer in solid tumors by disrupting the transport of calcium ions (Ca2+) in the endoplasmic reticulum or mitochondria, ultimately affecting cellular apoptosis. [ 36 ]…”

Section: Discussionmentioning

confidence: 99%

A prognostic signature associated with cell senescence predicts survival outcomes and strongly associates with immunotherapy and chemotherapy response in breast cancer

Pan

et al. 2023

Medicine

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The objective of this study is to assess the predictive potency of cell senescence-related genes (CSRGs) in breast cancer (BC) and establish a risk signature. Trascriptome data of CSRGs were obtained from the TCGA and GEO databases. Consensus clustering was used to generate CSRGs-based molecular clusters for BC patients. A CSRGs-derived risk signature was built using multiple Cox regression analyses of differentially expressed genes (DEGs) between clusters. The prognosis, immune infiltration, chemotherapy and immunotherapy response between different risk groups were analyzed and compared. Two molecular clusters of BC patients were generated on the basis of 79 differentially expressed CSRGs, which showed distinct prognosis and immune infiltration. A total of 1403 DEGs between the CSRGs-derived clusters were found, and 10 of them were independent prognostic genes that used to construct a risk signature. The results demonstrated that patients with older age and advanced stage presented with a higher risk scores. In addition, the risk signature was found to be associated with outcomes, immune infiltration, chemotherapy and immunotherapy response. Patients in the low-risk group showed a favorable prognosis and higher immunotherapy response than those in the high-risk group. Finally, we developed a highly stable nomogram that incorporates risk signature, chemotherapy, radiotherapy, and stage variables, enabling accurate prediction of the overall survival (OS) of individual patients. To conclude, the signature derived from CSRGs holds great promise as a biomarker for prognostic assessment of BC and may serve as a valuable tool in guiding immunotherapy.Abbreviations: BC = breast cancer, CCL19 = C-C motif chemokine ligand 19, CSRGs = cell senescence-related genes, DCs = dendritic cells, DEGs = differentially expressed genes, GO = gene ontology, IPS = immunophenoscore, KEGG = Kyoto encyclopedia of genes and genomes, NET = neutrophil extracellular trap, OS = overall survival, SHCBP1 = SHC binding and spindle-associated 1, TIDE = tumor immune dysfunction and exclusion.

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Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential

Cited by 5 publications

References 397 publications

Megakaryocyte maturation involves activation of the adaptive unfolded protein response

Megakaryocyte maturation involves activation of the adaptive unfolded protein response

Activating mutations in JAK2 and CALR differentially affect intracellular calcium flux in store operated calcium entry

A prognostic signature associated with cell senescence predicts survival outcomes and strongly associates with immunotherapy and chemotherapy response in breast cancer

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