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Cell Rep. 2015 Nov 24;13(8):1692-704. doi: 10.1016/j.celrep.2015.10.037. Epub 2015 Nov 12.

Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice.

Author information

1
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.
2
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
3
Whitehead Institute for Biomedical Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
4
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.
5
Department of Biological Sciences, Florida International University, Miami, FL 33199, USA.
6
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.
7
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.
8
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
9
Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33136, USA.
10
Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
11
Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA.
12
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.
13
Whitehead Institute for Biomedical Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: jaenisch@wi.mit.edu.
14
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: peng.jin@emory.edu.
15
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.

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.

PMID:
26586431
PMCID:
PMC4764044
DOI:
10.1016/j.celrep.2015.10.037
[Indexed for MEDLINE]
Free PMC Article

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