Acute loss of TET function results in aggressive myeloid cancer in mice

被引：139

作者：

An, Jungeun ^{[1
]}

Gonzalez-Avalos, Edahi ^{[1
]}

Chawla, Ashu ^{[1
]}

Jeong, Mira ^{[2
]}

Lopez-Moyado, Isaac F. ^{[1
]}

Li, Wei ^{[2
,3
,4
]}

Goodell, Margaret A. ^{[3
,4
]}

Chavez, Lukas ^{[1
,5
]}

Ko, Myunggon ^{[1
,6
]}

Rao, Anjana ^{[1
,7
,8
,9
]}

机构：

[1] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA

[2] Baylor Coll Med, Dept Pediat & Mol & Human Genet, Stem Cells & Regenerat Med Ctr, Houston, TX 77030 USA

[3] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA

[4] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[5] German Canc Res Ctr, Div Pediat Neurooncol, Computat Oncoepigen Grp, D-69120 Heidelberg, Germany

[6] Ulsan Natl Inst Sci & Technol, Sch Life Sci, Ulsan 689798, South Korea

[7] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

[8] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[9] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

HEMATOPOIETIC STEM-CELLS; METHYLCYTOSINE OXIDASES TET1; TUMOR-SUPPRESSOR; SELF-RENEWAL; DNA METHYLATION; DYNAMIC CHANGES; PROTEINS; 5-METHYLCYTOSINE; DIFFERENTIATION; MUTATIONS;

D O I：

10.1038/ncomms10071

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrity.

引用

页数：14

共 66 条

[1] Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies [J].

Abdel-Wahab, Omar ;

Mullally, Ann ;

Hedvat, Cyrus ;

Garcia-Manero, Guillermo ;

Patel, Jay ;

Wadleigh, Martha ;

Malinge, Sebastien ;

Yao, JinJuan ;

Kilpivaara, Outi ;

Bhat, Rukhmi ;

Huberman, Kety ;

Thomas, Sabrena ;

Dolgalev, Igor ;

Heguy, Adriana ;

Paietta, Elisabeth ;

Le Beau, Michelle M. ;

Beran, Miloslav ;

Tallman, Martin S. ;

Ebert, Benjamin L. ;

Kantarjian, Hagop M. ;

Stone, Richard M. ;

Gilliland, D. Gary ;

Crispino, John D. ;

Levine, Ross L. .

BLOOD, 2009, 114 (01) :144-147

[2] Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential:: A revised road map for adult blood lineage commitment [J].

Adolfsson, J ;

Månsson, R ;

Buza-Vidas, N ;

Hultquist, A ;

Liuba, K ;

Jensen, CT ;

Bryder, D ;

Yang, LP ;

Borge, OJ ;

Thoren, LAM ;

Anderson, K ;

Sitnicka, E ;

Sasaki, Y ;

Sigvardsson, M ;

Jacobsen, SEW .

CELL, 2005, 121 (02) :295-306

[3]

Bachman M, 2014, NAT CHEM, V6, P1049, DOI [10.1038/NCHEM.2064, 10.1038/nchem.2064]

[4] Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation [J].

Baubec, Tuncay ;

Colombo, Daniele F. ;

Wirbelauer, Christiane ;

Schmidt, Juliane ;

Burger, Lukas ;

Krebs, Arnaud R. ;

Akalin, Altuna ;

Schuebeler, Dirk .

NATURE, 2015, 520 (7546) :243-U278

[5] Notes on the role of dynamic DNA methylation in mammalian development [J].

Bestor, Timothy H. ;

Edwards, John R. ;

Boulard, Mathieu .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (22) :6796-6799

[6] CD48 on hematopoietic progenitors regulates stem cells and suppresses tumor formation [J].

Boles, Nathan C. ;

Lin, Kuanyin K. ;

Lukov, Georgi L. ;

Bowman, Teresa V. ;

Baldridge, Megan T. ;

Goodell, Margaret A. .

BLOOD, 2011, 118 (01) :80-87

[7] Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation [J].

Celik, Hamza ;

Mallaney, Cates ;

Kothari, Alok ;

Ostrander, Elizabeth L. ;

Eultgen, Elizabeth ;

Martens, Andrew ;

Miller, Christopher A. ;

Hundal, Jasreet ;

Klco, Jeffery M. ;

Challen, Grant A. .

BLOOD, 2015, 125 (04) :619-628

[8] Dnmt3a is essential for hematopoietic stem cell differentiation [J].

Challen, Grant A. ;

Sun, Deqiang ;

Jeong, Mira ;

Luo, Min ;

Jelinek, Jaroslav ;

Berg, Jonathan S. ;

Bock, Christoph ;

Vasanthakumar, Aparna ;

Gu, Hongcang ;

Xi, Yuanxin ;

Liang, Shoudan ;

Lu, Yue ;

Darlington, Gretchen J. ;

Meissner, Alexander ;

Issa, Jean-Pierre J. ;

Godley, Lucy A. ;

Li, Wei ;

Goodell, Margaret A. .

NATURE GENETICS, 2012, 44 (01) :23-U43

[9]

Chambers Stuart M, 2007, Cell Stem Cell, V1, P578, DOI 10.1016/j.stem.2007.10.003

[10] An Extensive Network of TET2-Targeting MicroRNAs Regulates Malignant Hematopoiesis [J].

Cheng, Jijun ;

Guo, Shangqin ;

Chen, Suning ;

Mastriano, Stephen J. ;

Liu, Chaochun ;

D'Alessio, Ana C. ;

Hysolli, Eriona ;

Guo, Yanwen ;

Yao, Hong ;

Megyola, Cynthia M. ;

Li, Dan ;

Liu, Jun ;

Pan, Wen ;

Roden, Christine A. ;

Zhou, Xiao-Ling ;

Heydari, Kartoosh ;

Chen, Jianjun ;

Park, In-Hyun ;

Ding, Ye ;

Zhang, Yi ;

Lu, Jun .

CELL REPORTS, 2013, 5 (02) :471-481

← 1 2 3 4 5 6 7 →