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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 IL7Rand 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 NOTCH1mutations 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.

The human β-catenin gene (CTNNB1) has been localized to 3p22→p21.3 by fluorescence in situ hybridization. Recent studies have suggested the presence of one or more tumor suppressor genes on the short arm of chromosome 3. This raises the possibility that CTNNB1, for which important features are already known, is involved in tumor progression.

The gene coding for human β-glucuronidase (GUSB) was mapped to 7q11.21→q11.22 by fluorescence in situ hybridization (FISH), thus clarifying the contradictory published localizations of this gene. Multiple unprocessed pseudogenes and pseudogene fragments for GUSB have been described. However, only two weak signals, one at chromosome band 5p13 and the other at 5q13, could be detected with FISH, suggesting considerable divergence between GUSB and its related sequences.

MYCLl has been previously mapped to lp32. This position was in contradiction with our mapping data of 1 p deletions in neuroblastoma cell lines. Using FISH on high resolution R-banded chromosomes with a YAC clone for MYCL1 we were able to reassign the gene to subband 1p34.3. This new map position is of importance for the establishment of an integrated map for chromosome 1 and the search for disease genes in this region.