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

• Type of Material: Article
• Authors: Zhigang Zhao, University of Miami; Li Chen, Emory University; Meelad M. Dawlaty, Massachusetts Institute of Technology; Feng Pan, University of Miami; Ophelia Weeks, Florida International University; Yuan Zhou, Institute of Hematology and Blood Diseases Hospital; Zeng Cao, Institute of Hematology and Blood Diseases Hospital; Hui Shi, University of Miami; Jiapeng Wang, Indiana University; Li Lin, Emory University; Shi Chen, University of Miami; Weiping Yuan, Institute of Hematology and Blood Diseases Hospital; Zhaohui Qin, Emory University; Hongyu Ni, University of Illinois at Chicago; Stephen D. Nimer, University of Miami; Feng-Chun Yang, University of Miami; Rudolf Jaenisch, Massachusetts Institute of Technology; Peng Jin, Emory University; Mingjiang Xu, University of Miami
• Language: English
• Date: 2015-11-24
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2015 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2015.10.037
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 13
• Issue: 8
• Start Page: 1692
• End Page: 1704
• Grant/Funding Information: This work was supported by grants from the NIH (HL112294 to M.X., CA172408 to M.X. and F.-C.Y., NS079625 and MH102690 to P.J., HDO45022 and CA084198 to R.J.), Simons Foundation (to R.J. and P.J.), and National Nature Science Foundation of China (#81328003 to W.Y.).; M.M.D. is a Damon Runyon Postdoctoral Fellow.
• Keywords: HEMATOPOIETIC STEM-CELLS; LEUKEMIA; METHYLATION; MAMMALIAN DNA; SELF-RENEWAL; Science & Technology; Cell Biology; Life Sciences & Biomedicine; DIFFERENTIATION; IN-VIVO; MOUSE; LEADS; 5-HYDROXYMETHYLCYTOSINE
• Research Categories: Biology, Cell; Health Sciences, Oncology; Health Sciences, Pathology

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 5hmC and 5mC 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.