Genomics

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TLX1 ChIP-Seq in ALL-SIL


ABSTRACT: The T-cell leukemia homeobox 1 (TLX1, HOX11) transcription factor is critically involved in the multistep pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanisms by which these T-cell specific oncogenes cooperate during transformation remain to be established. Here, we used an integrative genomics approach to show that the oncogenic properties of TLX1 are mediated by genome-wide interference with the ETS1 and RUNX1 transcription factors. Partial disruption of ETS1 and RUNX1 activity by ectopic TLX1 expression in immature thymocytes drives repression of T-cell specific super-enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 signaling. These phenomena coordinately trigger a TLX1 driven pre-leukemic phenotype in human thymic precursor cells, which corresponds with the in vivo thymic regression observed in murine TLX1 tumor models, and creates 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 multistep pathogenesis of TLX1 driven human leukemia. ChIP-sequencing data was generated for TLX1 in the T-ALL cell line ALL-SIL.

ORGANISM(S): Homo sapiens  

SUBMITTER: Kaat Durinck   Maté Ongenaert  Wouter Van Loocke  Frank Speleman  Pieter Rondou  Joni Van der Meulen  Pieter Van Vlierberghe 

PROVIDER: E-GEOD-62264 | ArrayExpress | 2015-08-05

SECONDARY ACCESSION(S): SRP048830GSE62264PRJNA263606

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

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

Durinck K K   Van Loocke W W   Van der Meulen J J   Van de Walle I I   Ongenaert M M   Rondou P P   Wallaert A A   de Bock C E CE   Van Roy N N   Poppe B B   Cools J J   Soulier J J   Taghon T T   Speleman F F   Van Vlierberghe P P  

Leukemia 20150625 12


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 integ  ...[more]

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