title: Repression of CDKN2C caused by PML/RARα binding promotes the proliferation and differentiation block in acute promyelocytic leukemia.
abstract: Inappropriate cell proliferation during oncogenesis is often accompanied by inactivation of components involved in the cell cycle machinery. Here, we report that cyclin-dependent kinase inhibitor 2C (CDKN2C) as a member of the cyclin-dependent kinase inhibitors is a target of the PML/RARα oncofusion protein in leukemogenesis of acute promyelocytic leukemia (APL).We found that CDKN2C was markedly downregulated in APL blasts compared with normal promyelocytes. Chromatin immunoprecipitation combined with quantitative polymerase chain reaction demonstrated that PML/RARα directly bound to the CDKN2C promoter in the APL patient-derived cell line NB4. Luciferase assays indicated that PML/RARα inhibited the CDKN2C promoter activity in a dose-dependent manner. Furthermore, all-trans retinoic acid treatment induced CDKN2C expression by releasing the PML/RARα binding on chromatin in NB4 cells. Functional studies showed that ectopic expression of CDKN2C induced a cell cycle arrest at the G0/G1phase and a partial differentiation in NB4 cells. Finally, the transcriptional regulation of CDKN2C was validated in primary APL patient samples. Collectively, this study highlights the importance of CDKN2C inactivation in the abnormal cell cycle progression and differentiation block of APL cells and may provide new insights into the study of pathogenesis and targeted therapy of APL.
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Jingming
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. yephero@hotmail.com.|Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China. yephero@hotmail.com.|Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. yephero@hotmail.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. kankanwang@shsmu.edu.cn.|Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China. kankanwang@shsmu.edu.cn.|Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. kankanwang@shsmu.edu.cn.
authors.forename: Kankan
authors.initials: K
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation; D049109:Cell Proliferation; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: C493971:CDKN2C protein, human; D050763:Cyclin-Dependent Kinase Inhibitor p18; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin
keywords: CDKN2C; acute promyelocytic leukemia; cell cycle arrest; differentiation