Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice
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 o...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/101657 |
| _version_ | 1826214078653136896 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 |
| author_sort | Zhao, Zhigang |
| collection | MIT |
| description | 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[superscript −/−] 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[superscript −/−] 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. |
| first_indexed | 2024-09-23T15:59:28Z |
| format | Article |
| id | mit-1721.1/101657 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:59:28Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1016572022-09-29T17:32:18Z Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice 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 Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Jaenisch, Rudolf 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[superscript −/−] 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[superscript −/−] 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. National Institutes of Health (U.S.) (Grant HDO45022) National Institutes of Health (U.S.) (Grant CA084198) Simons Foundation 2016-03-10T03:01:48Z 2016-03-10T03:01:48Z 2015-11 2015-08 Article http://purl.org/eprint/type/JournalArticle 22111247 http://hdl.handle.net/1721.1/101657 Zhao, Zhigang, Li Chen, Meelad M. Dawlaty, Feng Pan, Ophelia Weeks, Yuan Zhou, Zeng Cao, et al. “Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice.” Cell Reports 13, no. 8 (November 2015): 1692–1704. en_US http://dx.doi.org/10.1016/j.celrep.2015.10.037 Cell Reports Creative Commons Attribution http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | 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 Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice |
| title | Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice |
| title_full | Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice |
| title_fullStr | Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice |
| title_full_unstemmed | Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice |
| title_short | Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice |
| title_sort | combined loss of tet1 and tet2 promotes b cell but not myeloid malignancies in mice |
| url | http://hdl.handle.net/1721.1/101657 |
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