| Autor: |
Qian Kang, Dan Ma, Peng Zhao, Xiao Chai, Yi Huang, Rui Gao, Tianzhuo Zhang, Ping Liu, Bo Deng, Cheng Feng, Yan Zhang, Yinghao Lu, Yanju Li, Qin Fang, Jishi Wang |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Cell Death and Disease, Vol 15, Iss 8, Pp 1-14 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-4889 |
| DOI: |
10.1038/s41419-024-06996-w |
| Popis: |
Abstract Despite advancements in chemotherapy and the availability of novel therapies, the outcome of adult patients with B-cell acute lymphoblastic leukemia (B-ALL) remains unsatisfactory. Therefore, it is necessary to understand the molecular mechanisms underlying the progression of B-ALL. Brahma-related gene 1 (BRG1) is a poor prognostic factor for multiple cancers. Here, the expression of BRG1 was found to be higher in patients with B-ALL, irrespective of the molecular subtype, than in healthy individuals, and its overexpression was associated with a poor prognosis. Upregulation of BRG1 accelerated cell cycle progression into the S phase, resulting in increased cell proliferation, whereas its downregulation facilitated the apoptosis of B-ALL cells. Mechanistically, BRG1 occupies the transcriptional activation site of PPP2R1A, thereby inhibiting its expression and activating the PI3K/AKT signaling pathway to regulate the proto-oncogenes c-Myc and BCL-2. Consistently, silencing of BRG1 and administration of PFI-3 (a specific inhibitor targeting BRG1) significantly inhibited the progression of leukemia and effectively prolonged survival in cell-derived xenograft mouse models of B-ALL. Altogether, this study demonstrates that BRG1-induced overactivation of the PPP2R1A/PI3K/AKT signaling pathway plays an important role in promoting the progression of B-ALL. Therefore, targeting BRG1 represents a promising strategy for the treatment of B-ALL in adults. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
Full text from SpringerLink