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| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Xiao, Haowen Ding, Yingying Gao, Yang Wang, Li-Mengmeng Wang, Huafang Ding, Lijuan Li, Xiaoqing Yu, Xiaohong Huang, He |
| Abstract | Background Relapse represents the leading cause of death in both child and adult patients with acute lymphoblastic leukemia (ALL). Development of chemo-resistance is ultimately responsible for treatment failure and relapse, therefore understanding the molecular basis underlying resistance is imperative for developing innovative treatment strategies. Glucocorticoids (GCs) such dexamethasone and prednisolone are the backbone of combination chemotherapy regimens for treating all lymphoid tumors. However, the biological mechanisms of primary GC resistance in ALL is not completely understood. We previously performed a longitudinal whole-exome sequencing analysis on diagnosis/relapse pairs from adult patients with ALL. Our data revealed that relapse-specific truncation mutations in the NR3C1 gene, encoding the GC receptor, are frequently detected. Methods In the current study, we used discovery-based strategies including RNA sequencing (RNA-seq) and CRISPR/Cas9, followed by confirmatory testing, in human ALL cell lines, bone marrow blast samples from ALL patients and xenograft models, to elucidate the mechanisms responsible for resistance. Results Our results revealed a positive correlation between endogenous expression of NR3C1 in ALL cells and sensitivity to GCs and clinical outcomes. We further confirmed that ectopic expression of NR3C1 in ALL cells could reverse GC resistance, while deletion of NR3C1 confers resistance to GCs in ALL cell lines and xenograft models. RNA-seq analysis revealed a remarkable abundance of gene signatures involved in pathways in cancer, DNA replication, mismatch repair, P53 signalling, cell cycle, and apoptosis regulated by NR3C1. Significantly increased expression of pro-apoptotic genes including BCL2L11/Bim, BMF, BAD, BAX and BOK, and decreased transcription of anti-apoptotic genes including BCL2, BCL2L1 and BAG2 were observed in GC-resistant ALL cells following ectopic expression of NR3C1. Finally, we explored that GC resistance in ALL cells with haploinsufficiency of NR3C1 can be treated with Bcl-2 blockage. Conclusions Our findings suggest that the status of NR3C1 gene mutations and basal expression levels of NR3C1 in ALL cells are associated with sensitivity to GCs and clinical treatment outcomes. Early intervention strategies by rational combination of Bcl-2 blockage may constitute a promising new treatment option to GC-resistant ALL and significantly improving the chances of treating poor prednisone responders. |
| Related Links | https://cancerci.biomedcentral.com/counter/pdf/10.1186/s12935-019-0940-9.pdf |
| Ending Page | 13 |
| Page Count | 13 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 14752867 |
| DOI | 10.1186/s12935-019-0940-9 |
| Journal | Cancer Cell International |
| Issue Number | 1 |
| Volume Number | 19 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2019-08-23 |
| Access Restriction | Open |
| Subject Keyword | Cancer Research Cell Biology Haploinsufficiency NR3C1 Glucocorticoid resistance Acute lymphoblastic leukemia Mitochondrial apoptosis axis Bcl-2 blockage |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Genetics Oncology |
| Journal Impact Factor | 5.3/2023 |
| 5-Year Journal Impact Factor | 5/2023 |
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