scholarly journals miR-141-3p and TRAF5 Network Contributes to the Progression of T-Cell Acute Lymphoblastic Leukemia

2019 ◽  
Vol 28 (1_suppl) ◽  
pp. 59S-65S ◽  
Author(s):  
Ruiqing Zhou ◽  
Wenjian Mo ◽  
Shunqing Wang ◽  
Wei Zhou ◽  
Xiaowei Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Apoptosis ◽  
Lymphoblastic Leukemia ◽  
Tumor Necrosis Factor Receptor ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Cell Progression ◽  
Cell Acute Lymphoblastic Leukemia

Numerous lines of evidence have shown that microRNAs (miRNAs) play a vital role in regulating the progression in many types of cancers, including T cell acute lymphoblastic leukemia (T-ALL). In this study, the potential underlying mechanism and functional role of miR-141-3p in T-ALL cells were determined. We found that the expression level of miR-141-3p was significantly downregulated, while that of tumor necrosis factor receptor-associated factor 5 (TRAF5) was strongly upregulated in tissues from patients with T-ALL compared with healthy controls. Subsequently, upregulation of miR-141-3p significantly repressed T-ALL cell proliferation and promoted cell apoptosis. Conversely, downregulation of miR-141-3p significantly inhibited cell apoptosis and enhanced T-ALL cell proliferation. We also verified that TRAF5 was the direct target of miR-141-3p in T-ALL cells. Additionally, TRAF5 overexpression significantly repressed cell apoptosis and increased T-ALL cell proliferation. In summary, miR-141-3p regulates T-ALL cell progression by directly targeting TRAF5, and may serve as a potential therapeutic target for T-ALL.

scholarly journals ALKBH5-Mediated M6a-Demethylation Of USP1 Regulated T-Cell Acute Lymphoblastic Leukemia Cell Glucocorticoid Resistance by Stabilizing Aurora B

2021 ◽  
Author(s):  
Hongtao Gong ◽  
Liu Liu ◽  
Lina Cui ◽  
Hongyan Ma ◽  
Liyun Shen
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Invasion ◽  
Cell Apoptosis ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Glucocorticoid Resistance ◽  
Aurora B ◽  
Cell Sensitivity ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Recent studies have evidenced that ubiquitin-specific proteases (USPs) are associated with the occurrence and drug resistance of T-cell acute lymphoblastic leukemia (T-ALL). N6-methyladenosine (m6A) demethylase AlkB homolog 5 (ALKBH5) exerts a carcinogenic effect in human cancers and improves the mRNA stability of USPs. Whether ubiquitin specific protease 1 (USP1) controls chemoresistance in T-ALL is unknown. Our study demonstrated that USP1, Aurora kinase B (Aurora B) and ALKBH5 levels were highly expressed in glucocorticoid (GC)-resistant T-ALL patients and cells (CEM-C1). High expression of USP1 was correlated to the poor prognosis of T-ALL patients. Silencing USP1 increased CEM-C1 cell sensitivity to dexamethasone (Dex), reduced cell invasion, promoted cell apoptosis, and ameliorated glucocorticoid receptor (GR) expression. USP1 mediated T-ALL chemoresistance by interacting with Aurora B. Overexpression of USP1 reversed the promotive effects of Aurora B inhibitor on the sensitivity of CEM-C1 cells to Dex, cell apoptosis and GR level and the inhibition effect on cell invasion. Downregulation of ALKBH5 reduced the levels of USP1 and Aurora B, facilitated CEM-C1 cell sensitivity to Dex, apoptosis and GR expression, suppressed cell invasion. However, overexpression of USP1 reversed all the effects of ALKBH5 on CEM-C1 cells. In vivo results showed that tail vein injection of sh-USP1 resulted in a significant prolongation of mouse survival and maintained the normal weight of mice compared to the Dex group, reduced USP1 expression and facilitated GR expression. In conclusion, downregulation of USP1 ameliorated glucocorticoid resistance of T-cell acute lymphoblastic leukemia cells through suppressing Aurora B expression and elevating GR level.

scholarly journals LINC00511 exacerbated T-cell acute lymphoblastic leukemia via miR-195-5p/LRRK1 axis

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Shengli Li ◽  
Wenwen Guo ◽  
Huayun Geng ◽  
Chao Wang ◽  
Shuige Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Mediated Effects ◽  
Proliferation And Apoptosis ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Series Of Experiments ◽  
Non Coding Rnas

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a malignant disease arising from the abnormal proliferation of T lymphocyte in marrow. Long non-coding RNAs (lncRNAs) are one kind of non-coding RNAs (ncRNAs), which were reported to modulate the initiation or progression of diverse cancers. However, the role of LINC00511 in T-ALL was unknown. To figure out the function and mechanism of LINC00511 in T-ALL, a series of experiments were carried out. Based on the experimental results, we discovered that LINC00511 boosted cell proliferation and invasion, but hindered cell apoptosis in T-ALL cells. Besides, based on bio-informatics tool, miR-195-5p was selected for further exploration. Then, miR-195-5p was validated to bind with LINC00511. Hereafter, LRRK1 was testified to serve as a target gene of miR-195-5p. At last, rescue assays suggested that LRRK1 overexpression restored sh-LINC00511#1-mediated effects on cell proliferation and apoptosis. All in all, LINC00511 exacerbated T-ALL progression via miR-195-5p/LRRK1 axis, implying a potential therapeutic clue for the patients with T-ALL.

scholarly journals Function of SLC7A7 in T-Cell Acute Lymphoblastic Leukemia

2018 ◽  
Vol 48 (2) ◽  
pp. 731-740
Author(s):  
Xiaohui Ji ◽  
Xiaoyun Yang ◽  
Nan Wang ◽  
Meiyun Kang ◽  
Yaping Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Jurkat Cells ◽  
G1 Phase ◽  
Amino Acid Transport System ◽  
Cell Acute Lymphoblastic Leukemia

Background/Aims: Y+LAT1 protein, encoded by the SLC7A7 gene (a member of the SLC7 family), forms the cationic amino acid transport system y+L (system y+L). This system transports cationic amino acids such as arginine and lysine out of the cell. Arginine, in particular, is critical for T-cell activation and function in the immune response. Methods: We analyzed the role of the SLC7A7 gene in the cellular activities of Jurkat cells, specifically the cell cycle and cell proliferation, apoptosis, migration, and invasion. Cell proliferation was assessed using the Cell Counting Kit-8. Apoptosis and the cell cycle were determined with a FACSCalibur flow cytometer. A Transwell chamber was used to measure cell invasion and migration. Results: The proliferative ability of Jurkat cells was not significantly altered by transfection with SLC7A7 overexpression vectors. However, SLC7A7 overexpression significantly decreased the percentage of apoptotic Jurkat cells (P = 0.007) but significantly increased the proportion of G1 phase cells (P = 0.029) and cell migration (P < 0.001) and invasion (P < 0.001). Knockdown of SLC7A7 increased the cell apoptosis rate (P = 0.006) but decreased the G1 phase ratio (P = 0.002) and cell migration (P < 0.001) and invasion (P < 0.001). Conclusions: SLC7A7 plays a significant role in the pathogenesis of T-cell acute lymphoblastic leukemia.

NKX3.1 Is a Direct TAL1 Target Gene That Mediates the TAL1 Dependent Proliferation of Human T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 748-748
Author(s):  
Sophie Kusy ◽  
Nicolas Goardon ◽  
Florence Armstrong ◽  
Francoise Pflumio ◽  
paul-Henri Romeo
Keyword(s):  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Lines ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Regulatory Sequences ◽  
Human T Cell ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The TAL1/SCL gene encodes a bHLH (basic Helix-Loop-helix) protein that acts as a master gene in hematopoiesis. The TAL1/SCL gene is also the most frequently activated gene in human T-ALL but the oncogenic transcriptional programs, downstream of TAL1 in human T-ALL, are not well characterized. Using RNA interference to knockdown TAL1 expression, we show that TAL1 regulates both cell proliferation and death of human T-ALL cells. To determine the TAL1 target genes in human T-ALL, we combine TAL1 knockdown and gene expression profiling and show that TAL1 activates and repress a common subset of genes in cell lines. This subset includes known TAL1 target genes but also the NKX3.1 gene that is a homeobox gene, specifically expressed in the prostate epithelium during prostate development and in adulthood. NKX3.1 gene inactivation is one of the earliest events that occur in prostate cancer initiation, defining NKX3.1 as a major tumor suppressor gene of this cancer. TAL1 expression is associated with NKX3.1 activation in human T-ALL cell lines and NKX3.1 is expressed in TAL1 expressing human T-ALL blasts. TAL1 and GATA-3 are specifically bound in vivo to the [−870/−570] region of the human NKX3.1 gene promoter, and ex vivo, TAL1 can either directly binds an E-box [position −738] or be recruited by GATA-3 on a GATA binding site [position −697]. Finally, functional analyses of the NKX3.1 promoter indicate that these binding sites mediate the transcriptional activity of this promoter in T-cell lines. Sequences analysis of the human and mouse NKX3.1 promoters show that the regulatory sequences involved in the TAL1 activation of the human NKX3.1 gene are not conserved in the mouse gene, indicating why the NKX3.1 gene is not expressed in mouse models of TAL1 mediated leukemogenesis. NKX3.1 knockdown shows that NKX3.1 is necessary for the proliferation of TAL1 expressing T-ALL cell lines and NKX3.1 overexpression can complement the proliferation defects associated with TAL1 knockdown in T-ALL cell lines. Microarray analyses show that TAL1 and NKX3.1 regulate a common subset of genes in T-ALL that includes numerous genes encoding proteins known to be involved in T-cell proliferation and/or signaling. Finally, using a new culture system that enables proliferation of primary human leukemic cells, we show that the NKX3.1 gene is specifically activated in human TAL1 expressing T-ALL together with the defined potential TAL1 and/or NKX3.1 target genes. These results characterize NKX3.1 as the first gene directly activated by TAL1 and involved in the TAL1 dependent proliferation of human T-cell Acute Lymphoblastic Leukemia.

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