scholarly journals Epigenetic Modification of Death Receptor Genes for TRAIL and TRAIL Resistance in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 864
Author(s):  
Atsushi Watanabe ◽  
Kunio Miyake ◽  
Koshi Akahane ◽  
Kumiko Goi ◽  
Keiko Kagami ◽  
...  

Immunotherapies specific for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), such as anti-CD19 chimeric antigen receptor (CAR) T-cells and blinatumomab, have dramatically improved the therapeutic outcome in refractory cases. In the anti-leukemic activity of those immunotherapies, TNF-related apoptosis-inducing ligand (TRAIL) on cytotoxic T-cells plays an essential role by inducing apoptosis of the target leukemia cells through its death receptors (DR4 and DR5). Since there are CpG islands in the promoter regions, hypermethylation of the DR4 and DR5 genes may be involved in resistance of leukemia cells to immunotherapies due to TRAIL-resistance. We analyzed the DR4 and DR5 methylation status in 32 BCP-ALL cell lines by sequencing their bisulfite PCR products with a next-generation sequencer. The DR4 and DR5 methylation status was significantly associated with the gene and cell-surface expression levels and the TRAIL-sensitivities. In the clinical samples at diagnosis (459 cases in the NOPHO study), both DR4 and DR5 genes were unmethylated in the majority of cases, whereas methylated in several cases with dic(9;20), MLL-rearrangement, and hypodiploidy, suggesting that evaluation of methylation status of the DR4 and DR5 genes might be clinically informative to predict efficacy of immunotherapy in certain cases with such unfavorable karyotypes. These observations provide an epigenetic rational for clinical efficacy of immunotherapy in the vast majority of BCP-ALL cases.

2017 ◽  
Vol 94 ◽  
pp. 1077-1093 ◽  
Author(s):  
Fatemeh Alikarami ◽  
Majid Safa ◽  
Mohammad Faranoush ◽  
Parisa Hayat ◽  
Ahmad Kazemi

2014 ◽  
Vol 226 (06/07) ◽  
pp. 332-337 ◽  
Author(s):  
A. Troeger ◽  
L. Glouchkova ◽  
B. Ackermann ◽  
G. Escherich ◽  
H. Hanenberg ◽  
...  

Blood ◽  
2015 ◽  
Vol 126 (21) ◽  
pp. 2404-2414 ◽  
Author(s):  
Roel Polak ◽  
Bob de Rooij ◽  
Rob Pieters ◽  
Monique L. den Boer

Key Points Primary BCP-ALL cells use tunneling nanotubes to signal to mesenchymal stromal cells and thereby trigger cytokine secretion. Inhibiting tunneling nanotube signaling is a promising approach to induce apoptosis and sensitize BCP-ALL cells toward prednisolone.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lennart Lenk ◽  
Michela Carlet ◽  
Fotini Vogiatzi ◽  
Lea Spory ◽  
Dorothee Winterberg ◽  
...  

AbstractCentral nervous system (CNS) involvement remains a challenge in the diagnosis and treatment of acute lymphoblastic leukemia (ALL). In this study, we identify CD79a (also known as Igα), a signaling component of the preB cell receptor (preBCR), to be associated with CNS-infiltration and –relapse in B-cell precursor (BCP)-ALL patients. Furthermore, we show that downregulation of CD79a hampers the engraftment of leukemia cells in different murine xenograft models, particularly in the CNS.


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