Cellular senescence and hematological malignancies: From pathogenesis to therapeutics

Hu, Dawei; Yuan, Shunling; Zhong, Jing; Liu, Zhaoping; Wang, Yanyan; Liu, Li; Li, Junjun; Feng, Wen; Liu, Jing; Zhang, Ji

doi:10.1016/j.pharmthera.2021.107817

Cited by 23 publications

(26 citation statements)

References 151 publications

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“…The clinical data showed a strong correlation of MDS morbidity rates with by age, with the mid-age of 77 [17,30,44] . Here we highlighted the activities of HSPC aging in MDS etiopathology by assessing clinical HSPCs.…”

Section: Discussionmentioning

confidence: 89%

“…Nevertheless, our Lab has reported that total H3K27me3 level was signi cantly decreased in this patent model, as compared with the young group control [12] . MDS was viewed as the most relevant blood disease of hematopoietic senescence and the process of hematopoietic aging would qualitatively mimic MDS [17,30] . In any case, a causal link has not be a rmed between HSPC senescence and CDS pathogenesis, which features in heterogeneous myeloid disorders characterized by peripheral blood cytopenias and susceptibility to AML transformation [18] .…”

Section: Introductionmentioning

confidence: 99%

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Exploration of HSPC aging mechanism based upon in vitro cell modeling and MDS clinical sampling

Song

Zhao

et al. 2022

Preprint

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Background The pathogenetic mechanisms of Myelodysplastic Syndromes (MDS) were undefined. Hematopoietic senescence was manifested by association with malignant myeloid blood diseases, aging and immune dysfunction. Hematopoietic stem/progenitor cell (HSPC) aging was the primary determinant of hematopoietic senescence.MethodsIn current study, we used an in vitro HSPC aging mouse model that readily enabled the gather of a large number of aging HSPCs. The followed studies covered mRNA splicing and epigenetics (H3K27me3) relevant to HSPC aging, with methods such as Cut-tag, SA-β-gal assay, CFU-mix assay, RNA-seq, and RNAi knock down (KD). ResultsThe results showed that HSPC aging associated down-regulation of SR and hnRNPs family genes and mRNA splicing inhibitor (SSA) elicited HSPC aging-like phenotype. Cut-tag assay demonstrated that HSPCs aging was linked to global decline in H3K27me3 levels, which however, was systemically up-regulated in occupying the promoter of SR family and hnRNPs family genes. In addition, HSPCs aging exhibited alterations in the splicing patterns of TSS and SKIP.ConclusionsTogether, we proposed the linkages of HSPCs aging with epigenetic repression of SR and HnRNPs genes and inhibition of mRNA splicing pathway to alter TSS and SKIP-relevant alternative splicing. Our study provided insights to the etiopathology of MDS by exposing its connections to HSPC aging.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Exploration of HSPC aging mechanism based upon in vitro cell modeling and MDS clinical sampling

Song

Zhao

et al. 2022

Preprint

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“…Chronic persistent inflammation and inflammatory factors (e.g., IL-6) play an important role in MM [ 44 ]. Increasing evidence showed that cellular senescence and senescence-associated secretory phenotypes (SASP) establish a tumor environment that supports tumor cell proliferation and survival and promotes the development of multiple myeloma [ 45 ]. It has been established that poor nutritional status is a strong indicator of poor prognosis in MM [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Is RDW a clinically relevant prognostic factor for newly diagnosed multiple myeloma? A systematic review and meta-analysis

et al. 2022

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Background Multiple myeloma (MM) is an incurable plasma cell malignancy. Red cell distribution width (RDW) is a prognostic marker in various diseases, solid tumors, and hematologic neoplasms, but its prognostic significance in MM is controversial. In this study, we aimed to assess the relationship between RDW and the clinical prognosis of MM patients through a meta-analysis. Methods Relevant literature were retrieved from PubMed, Embase, and Web of Science databases according to PRISMA guideline. All relevant parameters were extracted and combined for statistical analysis. The effect size was presented as hazard ratio (HR)/odds ratio (OR) and 95% confidence interval (CI). HR/OR > 1 in MM patients with high RDW suggested a worse prognosis. Heterogeneity test evaluation was performed using Cochran's Q test and I2 statistics. A Pheterogeneity < 0.10 or I2 > 50% suggested significant heterogeneity. P < 0.05 was considered statistically significant. Statistical analysis was performed using Stata 12.0 software. Results 8 articles involving 9 studies with 1165 patients were included in our meta-analysis. Our results suggested that elevated RDW is significantly associated with poor prognosis in MM (OS: HR = 1.91, 95%CI: 1.48–2.46; PFS: HR = 2.87, 95% CI: 2.02–4.07). A significant correlation was not found between RDW and International Staging System (ISS) staging (ISS III VS ISS I-II: OR:1.53; 95%CI:0.97–2.42). Conclusion Our results suggested that RDW is a robust predictor of newly diagnosed MM outcomes.

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“…Predictive models according to gene expression profiles using mathematical and statistical modeling techniques have tremendous clinical potential. Cells undergo different types of senescence depending on the type of stress and/or stimulus, including stress-induced premature senescence (SIPS), oncogene-induced senescence (OIS), replicative senescence (RS), paracrine senescence (PS), treatment-induced senescence (TIS) and epigenetics-induced senescence (EIS) ( 24 ). Senescent cells collect in various organs and tissues with different physiological and pathological functions ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Establishment of three heterogeneous subtypes and a risk model of low-grade gliomas based on cell senescence-related genes

Chen

Yang

et al. 2022

Front. Immunol.

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BackgroundCellular senescence is a key element in the occurrence and progression of a variety of tumors. As a result, cellular senescence-related markers can be categorized based on the prognosis status of patients. Due to the heterogeneity and the complexity of the tumor microenvironment (TME), the long-term effectiveness of low-grade glioma (LGG) treatment remains a clinical challenge. Consequently, developing and refining effective treatment approaches to aid with LGG management is critical.MethodsBased on the expressions of cell senescence-related genes (CSRGs) acquired from the cellAge database, consensus clustering was utilized to identify stable molecular subtypes. Clinical features, immune infiltration, route modifications, and genetic changes of various subtypes were also assessed. Following that, the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression analysis were used for developing the cell senescence-related risk score (CSRS) model. Finally, a correlation study of the CSRS model with molecular, immunological, and immunotherapy parameters was performed.ResultsC1, C2, and C3, are the three senescence-related subtypes that were identified. Patients belonging to the C1 subtype had poor prognoses and a substantial proportion of them was in the grade G3. The differentially expressed genes (DEGs) among the three subtypes were used to develop the CSRS model. In both the training and independent validation cohort, the model had a high area under the receiver operating characteristic (ROC) curve in predicting the overall survival (OS) of patients. As a result, this model can predict clinical features and responses to immunotherapy in a variety of patients and it is a potential independent prognostic factor for LGG.ConclusionThis research discovered three LGG subtypes related to cell senescence and created a CSRS model for six genes. Cell senescence was highly associated with unfavorable prognosis in LGG. The CSRS model can be used to predict the prognosis of patients and identify patients who would benefit from immunotherapy.

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Cellular senescence and hematological malignancies: From pathogenesis to therapeutics

Cited by 23 publications

References 151 publications

Exploration of HSPC aging mechanism based upon in vitro cell modeling and MDS clinical sampling

Exploration of HSPC aging mechanism based upon in vitro cell modeling and MDS clinical sampling

Is RDW a clinically relevant prognostic factor for newly diagnosed multiple myeloma? A systematic review and meta-analysis

Establishment of three heterogeneous subtypes and a risk model of low-grade gliomas based on cell senescence-related genes

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