title: Loss of Dnmt3b accelerates MLL-AF9 leukemia progression.
abstract: Acute myeloid leukemia (AML) is a heterogeneous hematopoietic disorder with a poor prognosis. Abnormal DNA methylation is involved in the initiation and progression of AML. The de novo methyltransferases Dnmt3a and Dnmt3b are responsible for the generation of genomic methylation patterns. While DNMT3A is frequently mutated in hematological malignancies, DNMT3B is rarely mutated. Although it has been previously reported that Dnmt3b functions as a tumor suppressor in a mouse model of Myc-induced lymphomagenesis, its function in AML is yet to be determined. In this study, we demonstrated that deletion of Dnmt3b accelerated the progression of MLL-AF9 leukemia by increasing stemness and enhancing cell cycle progression. Gene profiling analysis revealed upregulation of the oncogenic gene set and downregulation of the cell differentiation gene set. Furthermore, loss of Dnmt3b was able to synergize with Dnmt3a deficiency in leukemia development. Taken together, these results demonstrate that Dnmt3b plays a tumor suppressive role in MLL-AF9 AML progression, thereby providing new insights into the roles of DNA methylation in leukemia development.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: P
authors.initials: P
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: F
authors.initials: F
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: S
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: H
authors.identifier: 0000-0003-4395-1095
authors.initials: H
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: S
authors.initials: S
authors.lastname: Hao
authors.affiliation: Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing, China.|Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Peking University, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.|Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
authors.forename: W
authors.identifier: 0000-0001-8288-5022
authors.initials: W
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.|Department of Medicine, Loma Linda University, Loma Linda, CA, USA.|Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.|Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.|Collaborative Innovation Center for Cancer Medicine, Tianjin, China.
authors.forename: T
authors.initials: T
authors.lastname: Cheng
mesh_terms: D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000378:metabolism*; D019175:DNA Methylation; D018450:Disease Progression; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion; D000097584:DNA Methyltransferase 3B; C474558:MLL-AF9 fusion protein, human