Title: Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia
Authors: Durinck, K
Van Loocke, W
Van der Meulen, J
Van de Walle, I
Ongenaert, M
Rondou, P
Wallaert, A
De Bock, Charles
Van Roy, N
Poppe, B
Cools, Jan
Soulier, J
Taghon, T
Speleman, F
Van Vlierberghe, P # ×
Issue Date: Dec-2015
Publisher: Nature Publishing Group
Series Title: Leukemia vol:29 issue:12 pages:2317-27
Article number: 10.1038/leu.2015.162
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.
ISSN: 0887-6924
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Molecular Biology of Leukemia (VIB-KU Leuven Center for Cancer Biology)
× corresponding author
# (joint) last author

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