Transcriptional regulation of survivin by c-Myc  in BCR/ABL-transformed cells:  implications in anti-leukaemic strategy.
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.
Fang
Zhi Hong
ZH
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Dong
Chun Lan
CL
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Chen
Zhong
Z
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Zhou
Bin
B
Cardiology Department, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Liu
Na
N
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Lan
Hai Feng
HF
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Liang
Lu
L
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Liao
Wen Bin
WB
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Zhang
Lei
L
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Han
Zhong Chao
ZC
State Key Laboratory of Experimental Hematology, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015398:Signal Transduction; D000077022:Survivin; D014158:Transcription, Genetic / Q000502:physiology*
C107489:BIRC5 protein, human; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D016271:Proto-Oncogene Proteins c-myc; D000077022:Survivin; D016044:Fusion Proteins, bcr-abl