Portal de Periódicos da CAPES

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

2015; Impact Journals LLC; Volume: 6; Issue: 29 Linguagem: Inglês

10.18632/oncotarget.4748

1949-2553

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

Chronic Lymphocytic Leukemia Research

// Lingbo Wang 1, 2 , Weili Cai 3 , Wei Zhang 2 , Xueying Chen 2 , Wenqian Dong 2 , Dongqi Tang 2 , Yun Zhang 2 , Chunyan Ji 1 , Mingxiang Zhang 2 1 Department of Hematology, Qilu Hospital, Shandong University, Jinan, China 2 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China 3 Department 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.