Oncotarget

Research Papers:

Inhibition of poly(ADP-ribose) polymerase 1 protects against acute myeloid leukemia by suppressing the myeloproliferative leukemia virus oncogene

Lingbo Wang _, Weili Cai, Wei Zhang, Xueying Chen, Wenqian Dong, Dongqi Tang, Yun Zhang, Chunyan Ji and Mingxiang Zhang

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:27490-27504. https://doi.org/10.18632/oncotarget.4748

Metrics: PDF 1053 views  |   HTML 1180 views  |   ?  


Abstract

Lingbo Wang1,2, Weili Cai3, Wei Zhang2, Xueying Chen2, Wenqian Dong2, Dongqi Tang2, Yun Zhang2, Chunyan Ji1, Mingxiang Zhang2

1Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

2The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China

3Department of Cardiology, The Third Hospital of Jinan, Jinan, China

Correspondence to:

Mingxiang Zhang, e-mail: zhangmingxiang@sdu.edu.cn

Chunyan Ji, e-mail: jichunyan@sdu.edu.cn

Keywords: PARP-1, MPL, acute myeloid leukemia, prognosis

Received: March 02, 2015     Accepted: July 13, 2015     Published: July 25, 2015

ABSTRACT

An abnormal expression of poly(ADP-ribose) polymerase 1 (PARP-1) has been described in many tumors. PARP-1 promotes tumorigenesis and cancer progression by acting on different molecular pathways. PARP-1 inhibitors can be used with radiotherapy or chemotherapy to enhance the susceptibility of tumor cells to the treatment. However, the specific mechanism of PARP-1 in acute myeloid leukemia (AML) remains unknown. Our study showed that expression of PARP-1 was upregulated in AML patients. PARP-1 inhibition slowed AML cell proliferation, arrested the cell cycle, induced apoptosis in vitro and improved AML prognosis in vivo. Mechanistically, microarray assay of AML cells with loss of PARP-1 function revealed that the myeloproliferative leukemia virus oncogene (MPL) was significantly downregulated. In human AML samples, MPL expression was increased, and gain-of-function and loss-of-function analysis demonstrated that MPL promoted cell growth. Moreover, PARP-1 and MPL expression were positively correlated in AML samples, and their overexpression was associated with an unfavorable prognosis. Furthermore, PARP-1 and MPL consistently acted on Akt and ERK1/2 pathways, and the anti-proliferative and pro-apoptotic function observed with PARP-1 inhibition were reversed in part via MPL activation upon thrombopoietin stimulation or gene overexpression. These data highlight the important function of PARP-1 in the progression of AML, which suggest PARP-1 as a potential target for AML treatment.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 4748