Transcriptional regulation of survivin by c-Myc in BCR/ABL-transformed cells: implications in anti-leukaemic strategy.

Journal Article (Journal Article)

BCR/ABL can cause chronic myelogenous leukaemia (CML) in part by altering the transcription of specific genes with growth- and/or survival-promoting functions. Recently, BCR/ABL has been shown to activate survivin, an important regulator of cell growth and survival, but the precise molecular mechanisms behind its expression and consequences thereof in CML cells remain unclear. Here, we reported that BCR/ABL promotes survivin expression and its cytoplasmic accumulation. The increase of survivin was largely controlled at the transcriptional level through a mechanism mediated by JAK2/PI3K signal pathways that activated c-Myc, leading to transactivation of survivin promoter. Dynamic down-regulation of survivin was a key event involved in imatinib-induced cell death while forced expression of survivin partially counteracted imatinib's effect on cell survival. Additionally, shRNA-mediated silencing of survivin or c-Myc eradicated colony formation of K562 cells in semi-solid culture system, implying an essential role for this transcriptional network in BCR/ABL-mediated cell transformation and survival. Finally, interruption of c-Myc activity by 10058-F4 exerted an anti-leukaemia effect with a synergistic interaction with imatinib and overcame the anti-apoptosis rescued by IL-3 supplement. In conclusion, we have identified JAK2/PI3K-mediated and c-Myc-dependent transactivation of survivin as a novel pathway in the transcriptional network orchestrated by BCR/ABL. These results suggest that the interference with this circuitry might be a potential utility for CML treatment.

Full Text

Duke Authors

Cited Authors

  • Fang, ZH; Dong, CL; Chen, Z; Zhou, B; Liu, N; Lan, HF; Liang, L; Liao, WB; Zhang, L; Han, ZC

Published Date

  • August 2009

Published In

Volume / Issue

  • 13 / 8B

Start / End Page

  • 2039 - 2052

PubMed ID

  • 19602047

Pubmed Central ID

  • PMC6512385

Electronic International Standard Serial Number (EISSN)

  • 1582-4934

Digital Object Identifier (DOI)

  • 10.1111/j.1582-4934.2008.00549.x

Language

  • eng

Conference Location

  • England