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

Zhigang Zhao | Zendy; Li Chen | Zendy; Meelad M. Dawlaty | Zendy; Feng Pan | Zendy; Ophelia Weeks | Zendy; Yuan Zhou | Zendy; Zeng Cao | Zendy; Hui Shi | Zendy; Jiapeng Wang | Zendy; Li Lin | Zendy; Shi Chen | Zendy; Weiping Yuan | Zendy; Zhaohui Qin | Zendy; Hongyu Ni | Zendy; Stephen D. Nimer | Zendy; FengChun Yang | Zendy; Rudolf Jaenisch | Zendy; Peng Jin | Zendy; Mingjiang Xu | Zendy

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

Author(s) -

Zhigang Zhao,

Li Chen,

Meelad M. Dawlaty,

Feng Pan,

Ophelia Weeks,

Yuan Zhou,

Zeng Cao,

Hui Shi,

Jiapeng Wang,

Li Lin,

Shi Chen,

Weiping Yuan,

Zhaohui Qin,

Hongyu Ni,

Stephen D. Nimer,

FengChun Yang,

Rudolf Jaenisch,

Peng Jin,

Mingjiang Xu

Publication year - 2015

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2015.10.037

Subject(s) - myeloid , cancer research , biology , lymphoma , carcinogenesis , leukemia , transcriptome , myeloid leukemia , gene , microbiology and biotechnology , gene expression , immunology , genetics

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.

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