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 The oxidation of (−)-epigallocatechin-3-gallate inhibits T-cell acute lymphoblastic leukemia cell line HPB-ALL via the regulation of Notch1 expression

RSC Advances ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 1679-1684 ◽  
Author(s):  
Yu-Na Wang ◽  
Jing Wang ◽  
Hao-Nan Yang ◽  
Bang-Lei Zhang ◽  
Pan Zhang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Line ◽  
Hematological Malignancy ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Activating Mutations ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia Cell Line

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and commonly associated with activating mutations in the Notch1 pathway.

Promotion and maintenance of leukemia by ERG

Blood ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3858-3868 ◽  
Author(s):  
Shinobu Tsuzuki ◽  
Osamu Taguchi ◽  
Masao Seto
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Chromosome 21 ◽  
Human Leukemia ◽  
General Role ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Adult Leukemia

Abstract The Ets-related gene (ERG) located on human chromosome 21 encodes a transcription factor and is thought to be causally related to Down syndrome–associated acute megakaryocytic leukemia in childhood. In clinical adult leukemia, however, increased expression of ERG is indicative of poor prognosis in T-cell acute lymphoblastic leukemia and cytogenetically normal acute myeloid leukemia, although the involvement of ERG in the development of adult leukemia remains elusive. Here, we show that forced expression of ERG in adult BM cells alters differentiation and induces expansion of T and erythroid cells and increases frequencies of myeloid progenitors in mouse BM transplantation models. The expanded T cells then develop T-cell acute lymphoblastic leukemia after acquisition of mutations in the Notch1 gene. Targeted expression of ERG into B cells also altered differentiation and promoted growth of precursor B cells. Overall, these findings suggest a general role of ERG in promoting growth of adult hematopoietic cells in various lineages. In line with this, shRNA-mediated silencing of ERG expression attenuated growth of human leukemia cell lines of various lineages. Thus, ERG is capable of promoting the development of leukemia and is crucial for its maintenance.

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.

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