title: Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice.
abstract: TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2 deletion in mice causes myeloid malignancies, while Tet1-null mice develop B cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 using Tet1/2 double-knockout (DKO) mice. DKO and Tet2(-/-) HSC/HPCs show overlapping and unique 5 hmC and 5 mC profiles. DKO mice exhibit strikingly decreased incidence and delayed onset of myeloid malignancies in comparison to Tet2(-/-) mice and in contrast develop lethal B cell malignancies. Transcriptome analysis of DKO tumors reveals expression changes in many genes dysregulated in human B cell malignancies, including LMO2, BCL6, and MYC. These results highlight the critical roles of TET1/2 individually and together in the pathogenesis of hematological malignancies.
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33136, USA; Department of Hematology and Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Whitehead Institute for Biomedical Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Meelad M
authors.initials: MM
authors.lastname: Dawlaty
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33136, USA; Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biological Sciences, Florida International University, Miami, FL 33199, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.affiliation: Department of Biological Sciences, Florida International University, Miami, FL 33199, USA.
authors.forename: Ophelia
authors.initials: O
authors.lastname: Weeks
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 300020, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
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 300020, China.
authors.forename: Zeng
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33136, USA; State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jiapeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33136, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
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 300020, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ni
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33136, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33136, USA; Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.affiliation: Whitehead Institute for Biomedical Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: jaenisch@wi.mit.edu.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: peng.jin@emory.edu.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33136, USA; Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: mxx51@miami.edu.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D019337:Hematologic Neoplasms / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; D003596:Cytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse