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

被引：84

作者：

Zhao, Zhigang ^{[1
,2
,3
]}

Chen, Li ^{[4
]}

Dawlaty, Meelad M. ^{[5
,6
]}

Pan, Feng ^{[1
,3
,7
]}

Weeks, Ophelia ^{[7
]}

Zhou, Yuan ^{[8
,9
,10
]}

Cao, Zeng ^{[8
,9
,10
]}

Shi, Hui ^{[1
,8
,9
,10
]}

Wang, Jiapeng ^{[3
]}

Lin, Li ^{[4
]}

Chen, Shi ^{[1
]}

Yuan, Weiping ^{[8
,9
,10
]}

Qin, Zhaohui ^{[11
]}

Ni, Hongyu ^{[12
]}

Nimer, Stephen D. ^{[1
]}

Yang, Feng-Chun ^{[1
,3
]}

Jaenisch, Rudolf ^{[5
,6
]}

Jin, Peng ^{[4
]}

Xu, Mingjiang ^{[1
,3
]}

机构：

[1] Univ Miami, Dept Biochem & Mol Biol, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[2] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Dept Hematol & Oncol, Key Lab Canc Prevent & Therapy, Tianjin 300060, Peoples R China

[3] Indiana Univ, Sch Med, Dept Pediat, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA

[4] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[5] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[6] MIT, Dept Biol, Cambridge, MA 02142 USA

[7] Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA

[8] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin 300020, Peoples R China

[9] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin 300020, Peoples R China

[10] Peking Union Med Coll, Tianjin 300020, Peoples R China

[11] Emory Clin, Rollins Sch Publ Hlth, Dept Biostatist & Bioinformat, Atlanta, GA 30322 USA

[12] Univ Illinois, Dept Pathol, Chicago, IL 60612 USA

来源：

CELL REPORTS | 2015年 / 13卷 / 08期

关键词：

HEMATOPOIETIC STEM-CELLS; MAMMALIAN DNA; SELF-RENEWAL; IN-VIVO; 5-HYDROXYMETHYLCYTOSINE; LEUKEMIA; LEADS; DIFFERENTIATION; METHYLATION; MOUSE;

D O I：

10.1016/j.celrep.2015.10.037

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 5hmC and 5mC profiles. DKO mice exhibit strikingly decreased incidence and delayed onset of myeloidmalignancies 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.

引用

页码：1692 / 1704

页数：13

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