Journal
LEUKEMIA
Volume 29, Issue 12, Pages 2317-2327Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.162
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Funding
- Fund for Scientific Research Flanders ('FWO Vlaanderen' research projects) [G.0202.09, G.0869.10N, 3G055013N, 3G056413N, 3GA00113N, 3G065614, G.0C47.13N, G0B2913N, G037514N, 3G002711]
- IWT Vlaanderen
- Ghent University (GOA grant) [01G01910]
- Cancer Plan from the Federal Public Service of Health
- Children Cancer Fund Ghent
- Belgian Program of Interuniversity Poles of Attraction [IUAP P7/03, P7/07]
- Canceropole IDF
- CIT program from the Ligue Contre le Cancer
- ERC St Grant Consolidator [311660]
- Saint-Louis Institute program [ANR-10-IBHU-0002]
- European Research Council (ERC) [311660] Funding Source: European Research Council (ERC)
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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.
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