The Route of Early T Cell Development: Crosstalk between Epigenetic and Transcription Factors

Chiara, Veronica Della; Daxinger, Lucia

doi:10.3390/cells10051074

Cited by 6 publications

(7 citation statements)

References 193 publications

(242 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multiple studies have uncovered the molecular phenomena behind the lineage plasticity of ETPs, and have designated certain genes as barcodes of particular specification programmes in these multipotent cells (Chiara et al, 2021;Hosokawa and Rothenberg, 2021). However, to the best of our knowledge, this study is the first of its kind to delineate the developmental pliability of the neoplastic forms of these multipotent cells, bringing forth new opportunities to subclassify multipotent ETP-ALL samples based on their lineage bias.…”

Section: Discussionmentioning

confidence: 98%

In Silico Integration of Transcriptome and Interactome Predicts an ETP-ALL-Specific Transcriptional Footprint that Decodes its Developmental Propensity

Mukherjee

Kar

Paul

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Early T precursor acute lymphoblastic leukemia (ETP-ALL) exhibits poor clinical outcomes and high relapse rates following conventional chemotherapeutic protocols. Extensive developmental flexibility of the multipotent ETP-ALL blasts with considerable intra-population heterogeneity in terms of immunophenotype and prognostic parameters might be a target for novel therapeutic interventions. Using a public gene expression dataset (GSE28703) from NCBI GEO DataSets with 12 ETP-ALL and 40 non-ETP-ALL samples, such heterogeneity was found to be reflected in their transcriptome as well. Hub genes were identified from the STRING-derived functional interaction network of genes showing differential expression between ETP-ALL and non-ETP-ALL as well as variable expression across ETP-ALL. Nine genes (KIT, HGF, NT5E, PROM1, CD33, ANPEP, CDH2, IL1B, and CXCL2) among the hubs were further validated as possible diagnostic ETP-ALL markers using another gene expression dataset (GSE78132) with 17 ETP-ALL and 27 non-ETP-ALL samples. Linear dimensionality reduction analysis with the expression levels of the hub genes in ETP-ALL revealed their divergent inclinations towards different hematopoietic lineages, proposing them as novel indicators of lineage specification in the incompletely differentiated ETP-ALL blasts. This further led to the formulation of a personalized lineage score calculation algorithm, which uncovered a considerable B-lineage-bias in a substantial fraction of ETP-ALL subjects from the GSE28703 and GSE78132 cohorts. In addition, STRING-derived physical interactome of the potential biomarkers displayed complete segregation of the B-lineage-skewed markers from other lineage-associated factors, highlighting their distinct functionality and possible druggability in ETP-ALL. A panel of these biomarkers might be useful in pinpointing the dominant lineage specification programmes in the ETP-ALL blasts on a personalized level, urging the development of novel lineage-directed precision therapies as well as repurposing of existing therapies against leukemia of different hematopoietic lineages; which might overcome the drawbacks of conventional chemotherapy.

show abstract

Section: Discussionmentioning

confidence: 98%

In Silico Integration of Transcriptome and Interactome Predicts an ETP-ALL-Specific Transcriptional Footprint that Decodes its Developmental Propensity

Mukherjee

Kar

Paul

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Additionally, CDR2 can be detected in vascular smooth muscle cells of rats and humans [ 33 ]. Interestingly, CD8+cytotoxic T cells will fail to activate T cells expressing CDR2 in response to epithelial cells expressing CDR2 [ 34 ]. Balamurugan et al indicated that the overexpression of the CDR2 gene plays an important role in repressing HIF-1 transactivation activity by interfering with p300 recruitment in their study on solid tumors [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…BCL11B was identified as an important role in T-cell function [ 34 ], and its lower expression is associated with adverse clinical outcomes for patients with myelodysplastic syndrome [ 36 ]. DUSP2 can control the activity of the transcription activator signal transducer and the activator of transcription 3 in its regulation of TH17 differentiation [ 37 ], and can also act as an immune checkpoint in T-cell antitumor immunity [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Human Transcriptome Array Analysis Identifies CDR2 as a Novel Suppressed Gene for Kawasaki Disease

et al. 2022

View full text Add to dashboard Cite

Kawasaki disease (KD) is a febrile childhood vasculitis that involves the coronary arteries. Most previous studies have focused on the genes activated in the acute phase of KD. However, in this study, we focused on suppressed genes in the acute stage of KD and identified novel targets with clinical significance and potential prognostic value for KD patients. We enrolled 18 patients with KD, 18 healthy controls (HC), and 18 febrile controls (FC) for human transcriptome array analysis. Another 19 healthy controls, 20 febrile controls, and 31 patients with KD were recruited for RT-PCR validation of target mRNA expressions. The results of Human Transcriptome Array (HTA) 2.0 showed 461 genes that were significantly higher in KD and then normalized after IVIG, as well as 99 suppressed genes in KD. Furthermore, we identified the four genes in KD with the most downregulation, including BCL11B, DUSP2, DDX24, and CDR2, as well as the upregulation of their expression following IVIG administration. The mRNA expression of CDR2 by qRT-PCR was the most compatible with the pattern of the HTA2.0 results. Furthermore, we found higher DDX24 mRNA expression in KD patients with CAL when compared to those without CAL 3 weeks after IVIG administration. In summary, activated gene expression represented a majority in the immune response of KD. In this study, we identified CDR2 as a novel suppressed gene for Kawasaki disease via human transcriptome array analysis and DDX24 associated with CAL formation, which may contribute to further understanding of CAL pathogenesis in KD.

show abstract

“…As one of the critical master regulators for T cell commitment in the thymus, TCF1 is the first T cell-specific transcription factor induced and activated by Notch signaling in the successive stage of T lineage specification, and it maintains a high expression level until T cell maturation (11,12). Activated TCF1 positively regulates two major target genes, B cell leukemia/lymphoma 11B (BCL11B) and GATA binding protein 3 (GATA3), to sustain T cell commitment and proliferation (13)(14)(15)(16)(17). Additionally, as pivotal T cell-specific transcription factors, TCF1 and BCL11B also participate in T cell activation and expansion (15,(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Decreased TCF1 and BCL11B expression predicts poor prognosis for patients with chronic lymphocytic leukemia

et al. 2022

View full text Add to dashboard Cite

T cell immune dysfunction is a prominent characteristic of chronic lymphocytic leukemia (CLL) and the main cause of failure for immunotherapy and multi-drug resistance. There remains a lack of specific biomarkers for evaluating T cell immune status with outcome for CLL patients. T cell factor 1 (TCF1, encoded by the TCF7 gene) can be used as a critical determinant of successful anti-tumor immunotherapy and a prognostic indicator in some solid tumors; however, the effects of TCF1 in CLL remain unclear. Here, we first analyzed the biological processes and functions of TCF1 and co-expressing genes using the GEO and STRING databases with the online tools Venny, Circos, and Database for Annotation, Visualization, and Integrated Discovery (DAVID). Then the expression and prognostic values of TCF1 and its partner gene B cell leukemia/lymphoma 11B (BCL11B) were explored for 505 CLL patients from 6 datasets and validated with 50 CLL patients from Henan cancer hospital (HNCH). TCF1 was downregulated in CLL patients, particularly in CD8+ T cells, which was significantly correlated with poor time-to-first treatment (TTFT) and overall survival (OS) as well as short restricted mean survival time (RMST). Function and pathway enrichment analysis revealed that TCF1 was positively correlated with BCL11B, which is involved in regulating the activation and differentiation of T cells in CLL patients. Intriguingly, BCL11B was highly consistent with TCF1 in its decreased expression and prediction of poor prognosis. More importantly, the combination of TCF1 and BCL11B could more accurately assess prognosis than either alone. Additionally, decreased TCF1 and BCL11B expression serves as an independent risk factor for rapid disease progression, coinciding with high-risk indicators, including unmutated IGHV, TP53 alteration, and advanced disease. Altogether, this study demonstrates that decreased TCF1 and BCL11B expression is significantly correlated with poor prognosis, which may be due to decreased TCF1+CD8+ T cells, impairing the effector CD8+ T cell differentiation regulated by TCF1/BCL11B.

show abstract

The Route of Early T Cell Development: Crosstalk between Epigenetic and Transcription Factors

Cited by 6 publications

References 193 publications

In Silico Integration of Transcriptome and Interactome Predicts an ETP-ALL-Specific Transcriptional Footprint that Decodes its Developmental Propensity

In Silico Integration of Transcriptome and Interactome Predicts an ETP-ALL-Specific Transcriptional Footprint that Decodes its Developmental Propensity

Human Transcriptome Array Analysis Identifies CDR2 as a Novel Suppressed Gene for Kawasaki Disease

Decreased TCF1 and BCL11B expression predicts poor prognosis for patients with chronic lymphocytic leukemia

Contact Info

Product

Resources

About