title: Inhibition of poly(ADP-ribose) polymerase 1 protects against acute myeloid leukemia by suppressing the myeloproliferative leukemia virus oncogene.
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.
authors: Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.|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.
authors: Lingbo
authors: L
authors: Wang
authors: Department of Cardiology, The Third Hospital of Jinan, Jinan, China.
authors: Weili
authors: W
authors: Cai
authors: 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.
authors: Wei
authors: W
authors: Zhang
authors: 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.
authors: Xueying
authors: X
authors: Chen
authors: 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.
authors: Wenqian
authors: W
authors: Dong
authors: 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.
authors: Dongqi
authors: D
authors: Tang
authors: 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.
authors: Yun
authors: Y
authors: Zhang
authors: Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
authors: Chunyan
authors: C
authors: Ji
authors: 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.
authors: Mingxiang
authors: M
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D049109:Cell Proliferation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D053628:Receptors, Thrombopoietin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: MPL; PARP-1; acute myeloid leukemia; prognosis