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The TLX1 oncogene drives aneuploidy in T cell transformation

Kim De Keersmaecker, Pedro J Real, Giusy Della Gatta, Teresa Palomero, Maria Luisa Sulis, Valeria Tosello, Pieter Van Vlierberghe UGent, Kelly Barnes, Mireia Castillo, Xavier Sole, et al. (2010) NATURE MEDICINE. 16(11). p.1321-U65
abstract
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
MUTATIONS, HOX11, TRANSGENIC MICE, GENE-EXPRESSION, ACUTE LYMPHOBLASTIC-LEUKEMIA, SURVIVAL, BCL11B, NOTCH1, LYMPHOMAGENESIS, LYMPHOCYTES
journal title
NATURE MEDICINE
Nat. Med.
volume
16
issue
11
pages
1321 - U65
Web of Science type
Article
Web of Science id
000283860100045
JCR category
MEDICINE, RESEARCH & EXPERIMENTAL
JCR impact factor
25.43 (2010)
JCR rank
1/105 (2010)
JCR quartile
1 (2010)
ISSN
1078-8956
DOI
10.1038/nm.2246
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1152571
handle
http://hdl.handle.net/1854/LU-1152571
date created
2011-02-16 11:50:12
date last changed
2016-12-19 15:45:24
@article{1152571,
  abstract     = {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.},
  author       = {De Keersmaecker, Kim and Real, Pedro J and Della Gatta, Giusy and Palomero, Teresa and Luisa Sulis, Maria and Tosello, Valeria and Van Vlierberghe, Pieter and Barnes, Kelly and Castillo, Mireia and Sole, Xavier and Hadler, Michael and Lenz, Jack and Aplan, Peter D and Kelliher, Michelle and Kee, Barbara L and Pandolfi, Pier Paolo and Kappes, Dietmar and Gounari, Fotini and Petrie, Howard and Van der Meulen, Joni and Speleman, Franki and Paietta, Elisabeth and Racevskis, Janis and Wiernik, Peter H and Rowe, Jacob M and Soulier, Jean and Avran, David and Cave, Helene and Dastugue, Nicole and Raimondi, Susana and Meijerink, Jules PP and Cordon-Cardo, Carlos and Califano, Andrea and Ferrando, Adolfo A},
  issn         = {1078-8956},
  journal      = {NATURE MEDICINE},
  keyword      = {MUTATIONS,HOX11,TRANSGENIC MICE,GENE-EXPRESSION,ACUTE LYMPHOBLASTIC-LEUKEMIA,SURVIVAL,BCL11B,NOTCH1,LYMPHOMAGENESIS,LYMPHOCYTES},
  language     = {eng},
  number       = {11},
  pages        = {1321--U65},
  title        = {The TLX1 oncogene drives aneuploidy in T cell transformation},
  url          = {http://dx.doi.org/10.1038/nm.2246},
  volume       = {16},
  year         = {2010},
}

Chicago
De Keersmaecker, Kim, Pedro J Real, Giusy Della Gatta, Teresa Palomero, Maria Luisa Sulis, Valeria Tosello, Pieter Van Vlierberghe, et al. 2010. “The TLX1 Oncogene Drives Aneuploidy in T Cell Transformation.” Nature Medicine 16 (11): 1321–U65.
APA
De Keersmaecker, K., Real, P. J., Della Gatta, G., Palomero, T., Luisa Sulis, M., Tosello, V., Van Vlierberghe, P., et al. (2010). The TLX1 oncogene drives aneuploidy in T cell transformation. NATURE MEDICINE, 16(11), 1321–U65.
Vancouver
1.
De Keersmaecker K, Real PJ, Della Gatta G, Palomero T, Luisa Sulis M, Tosello V, et al. The TLX1 oncogene drives aneuploidy in T cell transformation. NATURE MEDICINE. 2010;16(11):1321–U65.
MLA
De Keersmaecker, Kim, Pedro J Real, Giusy Della Gatta, et al. “The TLX1 Oncogene Drives Aneuploidy in T Cell Transformation.” NATURE MEDICINE 16.11 (2010): 1321–U65. Print.