Gamma Secretase Inhibitor: Therapeutic Target via NOTCH Signaling in T cell Acute Lymphoblastic Leukemia

2021 ◽  
Vol 22 ◽  
Author(s):  
Bhupendra Kaushik ◽  
Dilipkumar Pal ◽  
Supriyo Saha
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Notch Signalling ◽  
Molecular Techniques ◽  
Gamma Secretase ◽  
Pathway Activity ◽  
Secretase Inhibitor ◽  
Cell Acute Lymphoblastic Leukemia

Background: : T-cell acute lymphoblastic leukemia (T-ALL) is a disease which affects the bone marrow as well as lymphoblast which are expressed on T-cell immune phenotype. Diagnosis of T-ALL patients have shown that the disease presents large tumour burdens and leukemia cells in peripheral blood which often infiltrates into the central nervous system. Objective: Chemotherapy has been used as the main treatment method for this disease but with the recent research on molecular techniques, the studies have shown that NOTCH1 signalling could be a solution to this disease. NOTCH signalling undergoes non regulation in most T-ALL resulting to mutations in NOTCH1. Gamma-secretase (GS) plays a key role of blocking proteolytic activation of NOTCH receptors which could be a therapy for this kind of leukemia. This study thus aims at outlining the role of γ-secretase inhibitor via NOTCH signalling in T-ALL. Result and Conclusion: The role of GSI (γ-secretase inhibitor) in most T-ALL cell lines has been associate with pathway activity of NOTCH signalling. NOTCH1 mutation has however not served as a predictor of γ-secretase inhibitor sensitivity due to a number of factors including gene expression signature of NOTCH pathway activity which does not correlate. Despite the promise of this approach for NOTCH-1 activated T-ALL, not all patients with this condition would be expected to respond. Long-term therapeutic success in cancer is rarely achieved with monotherapy, and even targeting developmental pathways such as NOTCH will most likely require the development of combination regimens. Ultimately, the best use of these new therapeutic targeted agents, may become the next tools of ‘individualized medicine’.

scholarly journals PS917 SAFE TARGETING OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA BY SUBUNIT SELECTIVE GAMMA-SECRETASE INHIBITION

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 413-414
Author(s):  
C. de Bock ◽  
R. Habets ◽  
L. Serneels ◽  
I. Lodewijckx ◽  
D. Verbeke ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Gamma Secretase ◽  
Cell Acute Lymphoblastic Leukemia

Notch Signaling Represses Mir-223 in T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4630-4630
Author(s):  
Samuel D Gusscott ◽  
Florian Kuchenbauer ◽  
Andrew P Weng
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Growth ◽  
Notch Signaling ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Gamma Secretase ◽  
Protein Levels ◽  
Cell Acute Lymphoblastic Leukemia ◽  
T Cell Leukemogenesis

Abstract Abstract 4630 T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of the Notch1 signaling pathway. Several studies have utilized mRNA expression profiling to identify downstream mediators of oncogenic Notch signaling in this context. Since microRNAs (miRNAs) have in recent years been shown to play important roles in hematological maliganancy, we performed a microarray-based screen for Notch-dependent miRNA expression in T-ALL. Jurkat and P12-Ichikawa cell lines were treated with gamma-secretase inhibitor to block Notch signaling vs. DMSO control for 4 days and profiled using Exigon miRCURY LNA miRNA microarrays. Surprisingly few miRNAs were found to be regulated by this approach; however, one of the hits, miR-223, showed consistent upregulation after gamma-secretase treatment in Jurkat cells and 5 additional human T-ALL cell lines assessed by miRNA qPCR. This observation was unique to human T-ALL as murine models of T-ALL showed no evidence for Notch-dependent miR-223 expression. Given that canonical Notch signaling results in transcriptional activation, our observation that Notch signaling is associated with reduced miR-223 expression suggests an intermediary repressor may be involved. miR-223 has been reported to play an important role in normal granulopoiesis, to be expressed relatively highly in T-ALL with myeloid-like gene features, and most recently to accelerate Notch-mediated T-cell leukemogenesis. To explore potential functional consequences for Notch-dependent miR-223 repression in T-ALL, candidate miR-223 targets identified by TargetScan software were analyzed with Ingenuity Pathway Analysis software, which indicated IGF-1, insulin receptor, PTEN, and ERK5 signaling pathways as the top hits. We recently reported IGF1R signaling to be important for growth and viability of bulk T-ALL cells as well as for leukemia-initiating cell activity. Additionally, we reported that Notch signaling directly upregulates IGF1R transcription by binding to an intronic enhancer which is present between exons 21/22 in the human, but not mouse IGF1R locus. As miR-223 has previously been reported to target IGF1R mRNA and reduce its translation, we hypothesized that Notch signaling may also upregulate net IGF1R protein expression by repressing miR-223. To test this hypothesis, we transduced several human T-ALL cell lines with miR-223 retrovirus and observed a modest decrease in total IGF1R protein levels by western blot; however, no significant change was observed in surface IGF1R levels as assessed by flow cytometry. Addtionally, knockdown of miR-223 by lentiviral expression miR-223 target sequences (miR-223 “sponge”) resulted in modestly increased total IGF1R protein levels, but again showed no demonstrable effect on surface IGF1R levels. Of note, we also observed no apparent effect of either overexpression or knockdown of miR-223 on bulk cell growth or viability. We interpret these findings to suggest that Notch signaling does not have major effects on the miR transcriptome, and that up- or down-modulation of miR-223 in established T-ALL cells does not have significant effects on overall cell growth/viability. Further studies will be required to determine if miR-223 may act in concert with other Notch target genes to modulate cell physiology. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia

Haematologica ◽  
2020 ◽  
pp. haematol.2019.245639
Author(s):  
Chujing Zhang ◽  
Stella Amanda ◽  
Cheng Wang ◽  
Tze King Tan ◽  
Muhammad Zulfaqar Ali ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Aldehyde Dehydrogenase ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

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.

scholarly journals Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia

2016 ◽  
Vol 99 (6) ◽  
pp. 1077-1087 ◽  
Author(s):  
Tanja Rezzonico Jost ◽  
Chiara Borga ◽  
Enrico Radaelli ◽  
Andrea Romagnani ◽  
Lisa Perruzza ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia
Sign in / Sign up

Export Citation Format

Share Document