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Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia

Kaat Durinck (UGent) , Wouter Van Loocke (UGent) , Joni Van der Meulen (UGent) , Inge Van de Walle (UGent) , Maté Ongenaert (UGent) , Pieter Rondou (UGent) , Annelynn Wallaert (UGent) , CE de Bock, Nadine Van Roy (UGent) , Bruce Poppe (UGent) , et al.
(2015) LEUKEMIA. 29(12). p.2317-2327
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Abstract
The TLX1 transcription factor is critically involved in the multi-step pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanism by which these T-cell specific oncogenes cooperate during transformation remains to be established. Here, we used chromatin immunoprecipitation followed by sequencing to establish the genome-wide binding pattern of TLX1 in human T-ALL. This integrative genomics approach showed that ectopic TLX1 expression drives repression of T cell-specific enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 at critical target genes, including IL7R and NOTCH3. These phenomena coordinately trigger a TLX1-driven pre-leukemic phenotype in human thymic precursor cells, reminiscent of the thymus regression observed in murine TLX1 tumor models, and create a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multi-step pathogenesis of TLX1-driven human leukemia.
Keywords
TRANSCRIPTION FACTORS, SUPER-ENHANCERS, SELECTIVE-INHIBITION, GENE-EXPRESSION, TRANSFORMATION, DISRUPTION, ONCOGENES, SEQUENCES, IDENTITY, FEATURES

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MLA
Durinck, Kaat, et al. “Characterization of the Genome-Wide TLX1 Binding Profile in T-Cell Acute Lymphoblastic Leukemia.” LEUKEMIA, vol. 29, no. 12, 2015, pp. 2317–27, doi:10.1038/leu.2015.162.
APA
Durinck, K., Van Loocke, W., Van der Meulen, J., Van de Walle, I., Ongenaert, M., Rondou, P., … Van Vlierberghe, P. (2015). Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia. LEUKEMIA, 29(12), 2317–2327. https://doi.org/10.1038/leu.2015.162
Chicago author-date
Durinck, Kaat, Wouter Van Loocke, Joni Van der Meulen, Inge Van de Walle, Maté Ongenaert, Pieter Rondou, Annelynn Wallaert, et al. 2015. “Characterization of the Genome-Wide TLX1 Binding Profile in T-Cell Acute Lymphoblastic Leukemia.” LEUKEMIA 29 (12): 2317–27. https://doi.org/10.1038/leu.2015.162.
Chicago author-date (all authors)
Durinck, Kaat, Wouter Van Loocke, Joni Van der Meulen, Inge Van de Walle, Maté Ongenaert, Pieter Rondou, Annelynn Wallaert, CE de Bock, Nadine Van Roy, Bruce Poppe, J Cools, J Soulier, Tom Taghon, Franki Speleman, and Pieter Van Vlierberghe. 2015. “Characterization of the Genome-Wide TLX1 Binding Profile in T-Cell Acute Lymphoblastic Leukemia.” LEUKEMIA 29 (12): 2317–2327. doi:10.1038/leu.2015.162.
Vancouver
1.
Durinck K, Van Loocke W, Van der Meulen J, Van de Walle I, Ongenaert M, Rondou P, et al. Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia. LEUKEMIA. 2015;29(12):2317–27.
IEEE
[1]
K. Durinck et al., “Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia,” LEUKEMIA, vol. 29, no. 12, pp. 2317–2327, 2015.
@article{7066373,
  abstract     = {{The TLX1 transcription factor is critically involved in the multi-step pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanism by which these T-cell specific oncogenes cooperate during transformation remains to be established. Here, we used chromatin immunoprecipitation followed by sequencing to establish the genome-wide binding pattern of TLX1 in human T-ALL. This integrative genomics approach showed that ectopic TLX1 expression drives repression of T cell-specific enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 at critical target genes, including IL7R and NOTCH3. These phenomena coordinately trigger a TLX1-driven pre-leukemic phenotype in human thymic precursor cells, reminiscent of the thymus regression observed in murine TLX1 tumor models, and create a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multi-step pathogenesis of TLX1-driven human leukemia.}},
  author       = {{Durinck, Kaat and Van Loocke, Wouter and Van der Meulen, Joni and Van de Walle, Inge and Ongenaert, Maté and Rondou, Pieter and Wallaert, Annelynn and de Bock, CE and Van Roy, Nadine and Poppe, Bruce and Cools, J and Soulier, J and Taghon, Tom and Speleman, Franki and Van Vlierberghe, Pieter}},
  issn         = {{0887-6924}},
  journal      = {{LEUKEMIA}},
  keywords     = {{TRANSCRIPTION FACTORS,SUPER-ENHANCERS,SELECTIVE-INHIBITION,GENE-EXPRESSION,TRANSFORMATION,DISRUPTION,ONCOGENES,SEQUENCES,IDENTITY,FEATURES}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{2317--2327}},
  title        = {{Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia}},
  url          = {{http://doi.org/10.1038/leu.2015.162}},
  volume       = {{29}},
  year         = {{2015}},
}
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