scholarly journals Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway

2016 ◽  
Vol 9 (1) ◽  
Author(s):  
Annalisa Lonetti ◽  
Alessandra Cappellini ◽  
Alice Bertaina ◽  
Franco Locatelli ◽  
Andrea Pession ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Signaling Pathway ◽  
Lymphoblastic Leukemia ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Ruyue Zheng ◽  
Menglin Li ◽  
Shujuan Wang ◽  
Yanfang Liu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Signaling Pathway ◽  
Target Therapy ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Gene Mutations ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is one of the hematological malignancies. With the applications of chemotherapy regimens and allogeneic hematopoietic stem cell transplantation, the cure rate of T-ALL has been significantly improved. However, patients with relapsed and refractory T-ALL still lack effective treatment options. Gene mutations play an important role in T-ALL. The NOTCH1 gene mutation is the important one among these genetic mutations. Since the mutation of NOTCH1 gene is considered as a driving oncogene in T-ALL, targeting the NOTCH1 signaling patheway may be an effective option to overcome relapsed and refractory T-ALL. This review mainly summarizes the recent research advances of targeting on NOTCH1 signaling pathway in T-ALL.

scholarly journals Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

Leukemia ◽  
2013 ◽  
Vol 28 (4) ◽  
pp. 739-748 ◽  
Author(s):  
L M Neri ◽  
A Cani ◽  
A M Martelli ◽  
C Simioni ◽  
C Junghanss ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Signaling Pathway ◽  
Therapeutic Potential ◽  
Lymphoblastic Leukemia ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway

scholarly journals Interleukin-4 stimulates proliferation and growth of T-cell acute lymphoblastic leukemia cells by activating mTOR signaling

Leukemia ◽  
2008 ◽  
Vol 23 (1) ◽  
pp. 206-208 ◽  
Author(s):  
B A Cardoso ◽  
L R Martins ◽  
C I Santos ◽  
L M Nadler ◽  
V A Boussiotis ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Mtor Signaling ◽  
Interleukin 4 ◽  
Leukemia Cells ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Novel Ferrocene Derivatives Induce Apoptosis through Mitochondria-Dependent and Cell Cycle Arrest via PI3K/Akt/mTOR Signaling Pathway in T Cell Acute Lymphoblastic Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4677
Author(s):  
Liao Zeng ◽  
Mingqing Tang ◽  
Chao Pi ◽  
Jianrong Zheng ◽  
Sanxing Gao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signaling Pathway ◽  
Lymphoblastic Leukemia ◽  
Mtor Signaling ◽  
Jurkat Cells ◽  
G1 Phase ◽  
Mtor Signaling Pathway ◽  
Ferrocene Derivatives ◽  
Cycle Arrest ◽  
Cell Acute Lymphoblastic Leukemia

T cell acute lymphoblastic leukemia (T-ALL) is one of the most common causes of death in pediatric malignancies. However, the clinical chemotherapy for T-ALL has been limited by numerous side effects, emphasizing that novel anti-T-ALL drugs are urgently needed. Herein, a series of 2-acyl-1-dimethylaminomethyl-ferrocenes for cancer therapy have been evaluated. Among them, F1 and F3 exhibited potent cytotoxicity against T-ALL cell lines, especially Jurkat cells, with low cytotoxicity for normal cells. Further mechanistic studies revealed that F1 and F3 could induce apoptosis in Jurkat cells by destructing mitochondrial membrane, enhancing reactive oxygen species (ROS) generation, decreasing the Bcl-2/Bax ratio, releasing Cytochrome c, and increasing the expression of Cleaved Caspase-9/-3 and Cleaved PARP. Additionally, F1 and F3 could suppress cell proliferation and arrest the cell cycle at G0/G1 phase through the PI3K/Akt/mTOR signaling pathway by down-regulating the expression of CDK6, Cyclin D1, p-Akt, p-GSK-3β, p-mTOR, p-p70 S6K, and up-regulating the expression of P21 and P27, which would also be a possible mechanism. Consequently, ferrocene derivatives F1 and F3 could induce apoptosis through a mitochondria-dependent pathway mediated by ROS, and cell cycle arrest at G0/G1 phase via the PI3K/Akt/mTOR signaling pathway in Jurkat cells. The present study provided fundamental insights into the clinical application of F1 and F3 for the treatment of T-ALL.

scholarly journals DNA Methylation-Mediated Silencing of Mir-204 Enhances the Occurrence of T-Cell Acute Lymphoblastic Leukemia By Upregulating MMP-2 and MMP-9 through the NF-Κb Signaling Pathway

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Dabing Chen ◽  
Tingting Xiao ◽  
Dandan Lin ◽  
Haojie Zhu ◽  
Jingjing Xu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Matrix Metalloproteinase ◽  
Western Blot ◽  
Signaling Pathway ◽  
Promoter Region ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

Background : MicroRNAs (miR) are non-coding RNAs that play a role in regulation multiple functions in different cell types. Previous studies have shown that miR-204 is downregulated in T-ALL. We previously reported that matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) gene polymorphisms may be associated with the risk of T-cell acute lymphoblastic leukemia (T-ALL). The present study aims to decipher the role of miR-204 and MMP-2/MMP-9 in T-ALL occurrence to guide the diagnosis and treatment of T-ALL in the clinics. Methods: Expression of miR-204 was determined in the bone marrow and peripheral blood samples from 70 T-ALL patients and 70 healthy volunteers by real-time quantitative PCR (RT-qPCR). Bisulfite sequencing PCR (BSP) was used to detect the DNA methylation levels of the miR-204 promoter region in T-ALL patients and T-ALL cell lines.The effect of miR-204 on cell proliferation was evaluated with the cell counting kit-8 solution (CCK-8) assay and by Hoechst and PI double staining. The binding site of miR-204 on IRAK1 was predicted by the Primer Premier 5.0 and the defined binding sequences were used to construct luciferase-tag plasmids. The regulation of IRAK1 expression by miR-204 was evaluated by RT-qPCR and Western blot analysis. With the purpose to confirm the role of MMP-2 and MMP-9 in the occurrence of T-ALL, we investigated the effect of related proteins on T-ALL cells using Western blot. To determine that miR-204 affects the occurrence of T-ALL disease by regulating the NF-KB signaling pathway, RT-qPCR and Western Blot were used for verification. Results: DNA methylation directly affects the miR-204 expression in the promoter region when T-ALL developed. Moreover, overexpression of miR-204 inhibited the proliferation and enhanced the apoptosis of T-ALL cells. Notably, overexpression of miR-204 inhibited IRAK1, which in turn inhibited the proliferation and enhanced the apoptosis of T-ALL cells. Furthermore, IRAK1 enhanced the expression of MMP-2 and MMP-9 through phosphorylation of of p65 NF-κB, and miR-204 modulated MMP-2 and MMP-9 expression through the IRAK1/NF-κB signaling pathway. Conclusion s : Our results demonstrate that in T-ALL cells, DNA methylation-mediated silencing of miR-204 regulates the expression of MMP-2 and MMP-9 through increased transcription of IRAK1, and activation of the NF-κB signaling pathway. These data provide a potential mechanism for the role of MMP-2 and MMP-9 in the occurrence of T-ALL. Further studies will be needed to demonstrate whether demethylation of miR-204 may be a promising treatment for T-ALL. Disclosures No relevant conflicts of interest to declare.

Anti-Leukemia Effect of Rapamycin Alone or Plus Daunorubicin on Acute Lymphoblastic Leukemia Cell Lines

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3256-3256
Author(s):  
Xi Yang ◽  
Yuping Gong ◽  
Ting Niu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Line ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Ribosome Biogenesis ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway

Abstract Abstract 3256 Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine-threonine kinase that integrates signals from multiple inputs, including growth factors, amino acids, and intracellular energy supply, to regulate diverse cellular functions, such as transcription, ribosome biogenesis, translation initiation, and autophagic cell death (autophagy). Aberrant activation of the mTOR signaling pathway has been demonstrated in several tumors, including the majority of acute lymphoblastic leukemia(ALL). The potential anti-leukaemia effect of mTOR inhibitors has received some attention so far in ALL. In this study, we aimed to assess the anti-leukemic activity of Rapamycin (RAPA), an mTOR inhibitor, alone and in combination with daunorubicin (DNR). Here, we demonstrated that RAPA in concentrations of 1–100 nmol/L significantly inhibited the proliferation of Ph+ ALL cell line SUP-B15, whereas exerted poor effect on Ph- ALL cell line CEM. However, RAPA at a dose of 50 nmol/L significantly intensified the inhibition induced by DNR on two ALL cell lines. The synergistic effect was associated with regulation of autophagy and apoptosis, blockage of cell cycle progression in the G1 phase. We also reported that the consequence of DNR-treatment induced the overexpression of the mTOR signaling pathway in two ALL cell lines and primary leukemia cells in vitro, whereas RAPA effectively eliminated this deleterious side effect of the DNR and might enhance DNR ability to kill drug–resistant cancer. Altogether, our results suggested that DNR in combination with RAPA was more effective in the treatment of ALL than DNR alone. Therefore, combination of classical induction chemotherapy with an inhibitor of the mTOR kinase could be a promising strategy in future treatment of ALL. Disclosures: No relevant conflicts of interest to declare.

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