title: Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways.
abstract: Long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis, exemplified by the recent finding that lncRNA maternally expressed gene 3 (MEG3) inhibits tumor growth in a p53-dependent manner. Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults, and TP53 mutations or loss are frequently detected in patients with therapy-related AML or AML with complex karyotype. Here, we reveal that MEG3 is significantly downregulated in AML and suppresses leukemogenesis not only in a p53-dependent, but also a p53-independent manner. In addition, MEG3 is proven to be transcriptionally activated by Wilms' tumor 1 (WT1), dysregulation of which by epigenetic silencing or mutations is causally involved in AML. Therefore MEG3 is identified as a novel target of the WT1 molecule. Ten-eleven translocation-2 (TET2) mutations frequently occur in AML and significantly promote leukemogenesis of this disorder. In our study, TET2, acting as a cofactor of WT1, increases MEG3 expression. Taken together, our work demonstrates that TET2 dysregulated WT1-MEG3 axis significantly promotes AML leukemogenesis, paving a new avenue for diagnosis and treatment of AML patients.
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.|Department of Hematology, the Second Affiliated Hospital, Institute of Hematopoeitic Stem Cell Transplantation of Dalian Medical University, Liaoning Hematopoeitic Stem Cell Transplantation Medical Center, Dalian Key Laboratory of Hematology, Dalian Medical University, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lyu
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.|Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: J
authors.initials: J
authors.lastname: Lou
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.|Department of Hematology, the Second Affiliated Hospital, Institute of Hematopoeitic Stem Cell Transplantation of Dalian Medical University, Liaoning Hematopoeitic Stem Cell Transplantation Medical Center, Dalian Key Laboratory of Hematology, Dalian Medical University, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: J
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.|Department of Hematology, the Second Affiliated Hospital, Institute of Hematopoeitic Stem Cell Transplantation of Dalian Medical University, Liaoning Hematopoeitic Stem Cell Transplantation Medical Center, Dalian Key Laboratory of Hematology, Dalian Medical University, Dalian, China.
authors.forename: L
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.|Department of Hematology, the Second Affiliated Hospital, Institute of Hematopoeitic Stem Cell Transplantation of Dalian Medical University, Liaoning Hematopoeitic Stem Cell Transplantation Medical Center, Dalian Key Laboratory of Hematology, Dalian Medical University, Dalian, China.
authors.forename: D
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.|Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: B
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: D
authors.initials: D
authors.lastname: Zou
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.|Department of Hematology, the Second Affiliated Hospital, Institute of Hematopoeitic Stem Cell Transplantation of Dalian Medical University, Liaoning Hematopoeitic Stem Cell Transplantation Medical Center, Dalian Key Laboratory of Hematology, Dalian Medical University, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, the Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: E W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.|Department of Hematology, the Second Affiliated Hospital, Institute of Hematopoeitic Stem Cell Transplantation of Dalian Medical University, Liaoning Hematopoeitic Stem Cell Transplantation Medical Center, Dalian Key Laboratory of Hematology, Dalian Medical University, Dalian, China.
authors.forename: J
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: B
authors.initials: B
authors.lastname: Jin
mesh_terms: D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007438:Introns; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D025721:WT1 Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C498907:MEG3 non-coding RNA, human; D011518:Proto-Oncogene Proteins; D062085:RNA, Long Noncoding; D015534:Trans-Activators; D025721:WT1 Proteins; D049308:Dioxygenases; C541081:TET2 protein, human