Browsing by Author "Jaenisch, Rudolf"

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    Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice.
    (Elsevier, 2015-11-24) Zhao, Zhigang; Chen, Li; Dawlaty, Meelad M.; Pan, Feng; Weeks, Ophelia; Zhou, Yuan; Cao, Zeng; Shi, Hui; Wang, Jiapeng; Lin, Li; Chen, Shi; Yuan, Weiping; Qin, Zhaohui; Ni, Hongyu; Nimer, Stephen D.; Yang, Feng-Chun; Jaenisch, Rudolf; Jin, Peng; Xu, Mingjiang; Department of Pediatrics, IU School of Medicine
    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 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2−/− HSC/HPCs showed overlapping and unique 5hmC and 5mC profiles, and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed-onset of myeloid malignancies compared to Tet2−/− mice, and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1/2 individually and together via communication in the pathogenesis of hematological malignancies.