Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia

Bruserud, Øystein; Reikvam, Håkon

doi:10.3390/cancers15143711

Cited by 3 publications

(1 citation statement)

References 137 publications

(362 reference statements)

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“…Our phosphoproteomic studies suggest that a strong antiproliferative effect of V-ATPase inhibition is associated with high CK2 activity (Figure 4). Combination of V-ATPase and CK2 inhibition is further supported by several observations: (i) CK2 inhibition will cause an additional inhibition of several intracellular signaling pathways that are important in AML [132]; (ii) high CK2 activity seems to be a part of a chemoresistant AML cell phenotype and is associated with clinical…”

Section: Discussionmentioning

confidence: 82%

Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity

Bartaula-Brevik,

Leitch,

Hernandez-Valladares

et al. 2023

JCM

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Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated the functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) for primary AML cells derived from 80 consecutive patients. The V-ATPase inhibitors showed dose-dependent antiproliferative and proapoptotic effects that varied considerably between patients. A proteomic comparison of primary AML cells showing weak versus strong antiproliferative effects of V-ATPase inhibition showed a differential expression of proteins involved in intracellular transport/cytoskeleton functions, and an equivalent phosphoproteomic comparison showed a differential expression of proteins that regulate RNA processing/function together with increased activity of casein kinase 2. Patients with secondary AML, i.e., a heterogeneous subset with generally adverse prognosis and previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by a strong antiproliferative effect of V-ATPase inhibition and also by a specific mRNA expression profile of V-ATPase interactome proteins. Furthermore, the V-ATPase inhibition altered the constitutive extracellular release of several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), and increased mediator levels in the presence of AML-supporting bone marrow mesenchymal stem cells was then observed, especially for patients with secondary AML. Finally, animal studies suggested that the V-ATPase inhibitor bafilomycin had limited toxicity, even when combined with cytarabine. To conclude, V-ATPase inhibition has antileukemic effects in AML, but this effect varies between patients.

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Section: Discussionmentioning

confidence: 82%

Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity

Bartaula-Brevik,

Leitch,

Hernandez-Valladares

et al. 2023

JCM

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Claudin-2 upregulation enhances intestinal permeability, immune activation, dysbiosis, and mortality in sepsis

Oami,

Abtahi,

Shimazui

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Intestinal epithelial expression of the tight junction protein claudin-2, which forms paracellular cation and water channels, is precisely regulated during development and in disease. Here, we show that small intestinal epithelial claudin-2 expression is selectively upregulated in septic patients. Similar changes occurred in septic mice, where claudin-2 upregulation coincided with increased flux across the paracellular pore pathway. In order to define the significance of these changes, sepsis was induced in claudin-2 knockout (KO) and wild-type (WT) mice. Sepsis-induced increases in pore pathway permeability were prevented by claudin-2 KO. Moreover, claudin-2 deletion reduced interleukin-17 production and T cell activation and limited intestinal damage. These effects were associated with reduced numbers of neutrophils, macrophages, dendritic cells, and bacteria within the peritoneal fluid of septic claudin-2 KO mice. Most strikingly, claudin-2 deletion dramatically enhanced survival in sepsis. Finally, the microbial changes induced by sepsis were less pathogenic in claudin-2 KO mice as survival of healthy WT mice injected with cecal slurry collected from WT mice 24 h after sepsis was far worse than that of healthy WT mice injected with cecal slurry collected from claudin-2 KO mice 24 h after sepsis. Claudin-2 upregulation and increased pore pathway permeability are, therefore, key intermediates that contribute to development of dysbiosis, intestinal damage, inflammation, ineffective pathogen control, and increased mortality in sepsis. The striking impact of claudin-2 deletion on progression of the lethal cascade activated during sepsis suggests that claudin-2 may be an attractive therapeutic target in septic patients.

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Unlocking reproducible transcriptomic signatures for acute myeloid leukaemia: Integration, classification and drug repurposing

Chen,

Lu,

Wang

et al. 2024

J Cellular Molecular Medi

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Acute myeloid leukaemia (AML) is a highly heterogeneous disease, which lead to various findings in transcriptomic research. This study addresses these challenges by integrating 34 datasets, including 26 control groups, 6 prognostic datasets and 2 single‐cell RNA sequencing (scRNA‐seq) datasets to identify 10,000 AML‐related genes (ARGs). We focused on genes with low variability and high consistency and successfully discovered 191 AML signatures (ASs). Leveraging machine learning techniques, specifically the XGBoost model and our custom framework, we classified AML subtypes with both scRNA‐seq and bulk RNA‐seq data, complementing the ELN2022 classification approach. Our research also identified promising treatments for AML through drug repurposing, with solasonine showing potential efficacy for high‐risk AML patients, supported by molecular docking and transcriptomic analyses. To enhance reproducibility and customizability, we developed CSAMLdb, a user‐friendly database platform. It facilitates the reuse and personalized analysis of nearly all results obtained in this research, including single‐gene prognostics, multi‐gene scoring, enrichment analysis, machine learning risk assessment, drug repositioning analysis and literature abstract named entity recognition. CSAMLdb is available at http://www.csamldb.com.

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Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia

Cited by 3 publications

References 137 publications

Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity

Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity

Claudin-2 upregulation enhances intestinal permeability, immune activation, dysbiosis, and mortality in sepsis

Unlocking reproducible transcriptomic signatures for acute myeloid leukaemia: Integration, classification and drug repurposing

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