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

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; Feng Chun Yang; Rudolf Jaenisch; Peng Jin; Mingjiang Xu

doi:10.1016/j.celrep.2015.10.037

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

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
, Feng Chun Yang
, Rudolf Jaenisch
, Peng Jin
, Mingjiang Xu

Research output: Contribution to journal › Article › peer-review

90 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1692-1704
Number of pages	13
Journal	Cell Reports
Volume	13
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2015.10.037
State	Published - Nov 24 2015
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2015.10.037

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Zhao, Z., Chen, L., Dawlaty, M. M., Pan, F., Weeks, O., Zhou, Y., Cao, Z., Shi, H., Wang, J., Lin, L., Chen, S., Yuan, W., Qin, Z., Ni, H., Nimer, S. D., Yang, F. C., Jaenisch, R., Jin, P., & Xu, M. (2015). Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice. Cell Reports, 13(8), 1692-1704. https://doi.org/10.1016/j.celrep.2015.10.037

@article{96555fb128b54d759369f1a04a3a7a4a,

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

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.",

author = "Zhigang Zhao and Li Chen and Dawlaty, \{Meelad M.\} and Feng Pan and Ophelia Weeks and Yuan Zhou and Zeng Cao and Hui Shi and Jiapeng Wang and Li Lin and Shi Chen and Weiping Yuan and Zhaohui Qin and Hongyu Ni and Nimer, \{Stephen D.\} and Yang, \{Feng Chun\} and Rudolf Jaenisch and Peng Jin and Mingjiang Xu",

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year = "2015",

month = nov,

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doi = "10.1016/j.celrep.2015.10.037",

language = "English (US)",

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T1 - Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice

AU - Zhao, Zhigang

AU - Chen, Li

AU - Dawlaty, Meelad M.

AU - Pan, Feng

AU - Weeks, Ophelia

AU - Zhou, Yuan

AU - Cao, Zeng

AU - Shi, Hui

AU - Wang, Jiapeng

AU - Lin, Li

AU - Chen, Shi

AU - Yuan, Weiping

AU - Qin, Zhaohui

AU - Ni, Hongyu

AU - Nimer, Stephen D.

AU - Yang, Feng Chun

AU - Jaenisch, Rudolf

AU - Jin, Peng

AU - Xu, Mingjiang

PY - 2015/11/24

Y1 - 2015/11/24

N2 - 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.

AB - 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.

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C2 - 26586431

AN - SCOPUS:84952874773

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JO - Cell Reports

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ER -

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

Abstract

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