Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Hematology, TRANSCRIPTION FACTORS, SELECTIVE-INHIBITION, SUPER-ENHANCERS, GENE, DISRUPTION, EXPRESSION, ONCOGENES, SEQUENCES, IDENTITY, Cell Line, Tumor, Chromatin Immunoprecipitation, Homeodomain Proteins, Humans, Oncogenes, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins, Receptor, Notch1, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, Immunology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences, 3211 Oncology and carcinogenesis

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.