Identification of signature genes and drug candidates for primary plasma cell leukemia: An integrated system biology approach

Chaudhary, Raushan Kumar; Patil, Prakash; Ananthesh, L; Mahendra, G. S.; Mateti, Uday Venkat; Shetty, Vijith; Khanal, Pukar

doi:10.1016/j.compbiomed.2023.107090

Cited by 6 publications

(1 citation statement)

References 37 publications

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“…These AGING techniques leverage complex biological data and extensive datasets to identify molecular signatures associated with various cancer types, improving early and precise cancer diagnostics. Furthermore, they assist in modeling cancer progression, predicting patient outcomes, and refining personalized treatment approaches through data-driven analyses and machine learning [28][29][30][31]. At present, the investigation of NB subtypes through immune microenvironment transcriptomic features is ongoing, the integration of computational methodologies and transcriptome data plays a crucial role in understanding the heterogeneity of the NB microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Immune microenvironment heterogeneity reveals distinct subtypes in neuroblastoma: insights into prognosis and therapeutic targets

Yang,

Li,

Zheng

et al. 2023

Aging

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Background: Neuroblastoma (NB) is a childhood cancer originating from immature nerve cells in the sympathetic nervous system. Current clinical and molecular subtyping methods for NB have limitations in providing accurate prognostic information and guiding treatment decisions. Results: To overcome these challenges, we explored the microenvironment of NB based on the knowledge-based functional gene expression signatures (Fges), which revealed heterogeneous subtypes. Consensus clustering of Fges activity scores identified three subtypes (Cluster 1, Cluster 2, and Cluster 3) that demonstrated significant differences in prognosis compared to mainstream subtypes. We assessed the immune infiltration, immunogenicity, CD8T cytotoxicity, and tumor purity of these subtypes, uncovering their distinct biological functions. Cluster 1 and Cluster 2 exhibited higher immunoreactivity, while Cluster 3 displayed higher tumor purity and poor prognosis. Gene ontology annotation and pathway analysis identified immune activation in Cluster 1, epithelial-mesenchymal transition (EMT) in Cluster 2, and cell cycle processes in Cluster 3. Notably, the impact of EMT activity on prognosis may vary across NB subtypes. A classification model using XGBoost accurately predicted subtypes in independent NB cohorts, with significant prognostic differences. GPR125 , CDK4 , and GREB1 emerged as potential therapeutic targets in Cluster 3. CD4K inhibitors showed subtype-specific responses, suggesting tailored treatment strategies. Single-cell analysis highlighted unfavorable clinical features in Cluster 3, including high-risk classification and reduced cytotoxicity. Suppressed interactions between monocytes, macrophages, and regulatory T cells were observed, affecting immune regulation and patient prognosis. Conclusion: To summarize, we have identified a new independent prognostic factor in NB that underscores the significant correlation between tumor phenotype and immune contexture. These findings deepen our understanding of NB subtypes and immune cell interactions, paving the way for more effective treatment approaches.

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Section: Introductionmentioning

confidence: 99%

Immune microenvironment heterogeneity reveals distinct subtypes in neuroblastoma: insights into prognosis and therapeutic targets

Yang,

Li,

Zheng

et al. 2023

Aging

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Assessing the reproducibility of machine-learning-based biomarker discovery in Parkinson’s disease

Ameli,

Peña-Castillo,

Usefi

2024

Computers in Biology and Medicine

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Exploring the globoid cell leukodystrophy protein network and therapeutic interventions

Khanal,

Patil,

Bhattacharya

et al. 2024

Sci Rep

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Globoid cell leukodystrophy is a severe rare disorder characterized by white matter degradation, resulting in a progressive loss of physical and mental abilities and has extremely limited therapeutic interventions. Therefore, this study aimed to delve into the Globoid cell leukodystrophy associated intricate network of differentially expressed genes (p < 0.05, |Fc|> 1) to identify potential druggable targets and possible therapeutic interventions using small molecules. The disease-associated neuronal protein circuit was constructed and analyzed, identifying 53 nodes (minimum edge cutoff 1), among which five (FOS, FOSB, GDNF, GFRA1, and JUN) were discerned as potential core protein nodes.Although our research enumerates the potential small molecules to target various protein nodes in the proposed disease network, we particularly underscore T-5224 to inhibit c-Jun activity as JUN was identified as one of the pivotal elements within the disease-associated neuronal protein circuit. The evaluation of T-5224 binding energy (− 11.0 kcal/mol) from docking study revealed that the compound to exhibit a notable affinity towards Jun/CRE complex. Moreover, the structural integrity of complex was affirmed through comprehensive molecular dynamics simulations, indicating a stable hydrophilic interaction between T-5224 and the Jun/CRE complex, thereby enhancing protein compactness and reducing solvent accessibility. This binding energy was further substantiated by free binding analysis, revealing a substantial thermodynamics complex state (− 448.00 ± 41.73 kJ/mol). Given that this investigation is confined to a computational framework, we additionally propose a hypothetical framework to ascertain the feasibility of inhibiting the Jun/CRE complex with T-5224 against Globoid cell leukodystrophy, employing a combination of in vitro and in vivo methodologies as a prospective avenue of this study.

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Identification of signature genes and drug candidates for primary plasma cell leukemia: An integrated system biology approach

Cited by 6 publications

References 37 publications

Immune microenvironment heterogeneity reveals distinct subtypes in neuroblastoma: insights into prognosis and therapeutic targets

Immune microenvironment heterogeneity reveals distinct subtypes in neuroblastoma: insights into prognosis and therapeutic targets

Assessing the reproducibility of machine-learning-based biomarker discovery in Parkinson’s disease

Exploring the globoid cell leukodystrophy protein network and therapeutic interventions

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