The TLX1 oncogene drives aneuploidy in T cell transformation

被引：112

作者：

De Keersmaecker, Kim ^{[1
,2
,3
]}

Real, Pedro J. ^{[1
]}

Della Gatta, Giusy ^{[1
]}

Palomero, Teresa ^{[1
,4
]}

Luisa Sulis, Maria ^{[1
,5
]}

Tosello, Valeria ^{[1
]}

Van Vlierberghe, Pieter ^{[1
]}

Barnes, Kelly ^{[1
]}

Castillo, Mireia ^{[4
]}

Sole, Xavier ^{[6
,7
]}

Hadler, Michael ^{[1
]}

Lenz, Jack ^{[8
]}

Aplan, Peter D. ^{[9
]}

Kelliher, Michelle ^{[10
]}

Kee, Barbara L. ^{[11
]}

Pandolfi, Pier Paolo ^{[12
,13
]}

Kappes, Dietmar ^{[14
]}

Gounari, Fotini ^{[15
]}

Petrie, Howard ^{[16
]}

Van der Meulen, Joni ^{[17
]}

Speleman, Frank ^{[17
]}

Paietta, Elisabeth ^{[18
,19
]}

Racevskis, Janis ^{[18
,19
]}

Wiernik, Peter H. ^{[18
,19
]}

Rowe, Jacob M. ^{[20
,29
]}

Soulier, Jean ^{[21
,22
,23
]}

Avran, David ^{[21
,22
,23
]}

Cave, Helene ^{[24
]}

Dastugue, Nicole ^{[25
]}

Raimondi, Susana ^{[26
]}

Meijerink, Jules P. P. ^{[27
]}

Cordon-Cardo, Carlos ^{[4
]}

Califano, Andrea ^{[1
,28
]}

Ferrando, Adolfo A. ^{[1
,4
,5
]}

机构：

[1] Columbia Univ, Inst Canc Genet, New York, NY 10027 USA

[2] VIB, Dept Mol & Dev Genet, Louvain, Belgium

[3] Katholieke Univ Leuven, Ctr Human Genet, Louvain, Belgium

[4] Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA

[5] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA

[6] Inst Invest Biomed Bellvitge, Biomarkers & Susceptibil Unit, Catalan Inst Oncol, Barcelona, Spain

[7] IDIBELL, Biomed Res Ctr Network Epidemiol & Publ Hlth, Catalan Inst Oncol, Barcelona, Spain

[8] Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10467 USA

[9] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[10] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA USA

[11] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA

[12] Harvard Univ, Sch Med, Dept Med, Beth Israel Deaconess Canc Ctr, Boston, MA USA

[13] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Canc Ctr, Boston, MA 02115 USA

[14] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA

[15] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[16] Scripps Res Inst, Dept Canc Biol, Jupiter, FL USA

[17] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium

[18] Montefiore Med Ctr, North Div, New York, NY USA

[19] New York Med Coll, New York, NY USA

[20] Technion Israel Inst Technol, Haifa, Israel

[21] Hop St Louis, AP HP, Hematol Lab, Paris, France

[22] Hop St Louis, INSERM, U944, Paris, France

[23] Univ Paris 07, Hop St Louis, Inst Univ Hematol, Paris, France

[24] Univ Paris 07, Hop Robert Debre, AP HP, Dept Genet, Paris, France

[25] Hop Purpan, Hematol Lab, Toulouse, France

[26] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[27] Sophia Childrens Univ Hosp, Erasmus MC, Dept Pediat Oncol Hematol, Rotterdam, Netherlands

[28] Columbia Univ, Joint Ctr Syst Biol, New York, NY USA

[29] Rambam Med Ctr, Haifa, Israel

来源：

NATURE MEDICINE | 2010年 / 16卷 / 11期

基金：

美国国家卫生研究院;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; GENE-EXPRESSION; MUTATIONS; HOX11; BCL11B; NOTCH1; LYMPHOMAGENESIS; SELECTION; RECURRENT; PATHWAYS;

D O I：

10.1038/nm.2246

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The TLX1 oncogene (encoding the transcription factor T cell leukemia homeobox protein-1) has a major role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T cell transformation downstream of TLX1 remain to be elucidated. Here we show that transgenic expression of human TLX1 in mice induces T-ALL with frequent deletions and mutations in Bcl11b (encoding B cell leukemia/lymphoma-11B) and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 (encoding CHK1 checkpoint homolog) and additional mitotic control genes and induces loss of the mitotic checkpoint in nontransformed preleukemic thymocytes. These results identify a previously unrecognized mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.

引用

页码：1321 / +

页数：8

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