Tumor-specific rearrangement of the TAL1 gene is the most common genetic defect associated with T-cell acute lymphoblastic leukemia (T-ALL). These rearrangements arise by chromosome translocation (about 3% of T-ALL patients) or local DNA recombination (about 25% of T-ALL patients), and they result in the inappropriate expression of TAL1 gene products in the malignant cells of these patients. Preliminary data suggests that TAL1 activation may also occur in the absence of detectable DNA alterations. Therefore, a long term goal of this project is to determine the incidence and nature of TAL1 gene activation in a large cohort of T-ALL patients. Furthermore, since these alterations are tumor-specific, preliminary data suggests that residual or re-emergent leukemia could be monitored using PCR-based methods to detect cells with TAL1 gene rearrangements. Accordingly, the Pediatric Oncology Group has approved incorporation of this study to monitor residual disease within treatment protocols for newly-diagnosed T-ALL. The long-term objective of this study is to determine if clinical relapse can be predicted by this approach during treatment for T-ALL. TAL1 encodes the basic helix-loop helix (HLH) motif, a DNA-binding and protein-dimerization domain common to several known transcriptional regulatory factors. TAL1 polypeptides interact stably with HLH proteins encoded by the E2A gene (E12 and E47). The resultant heterodimers (TAL1/E12 and TAL1/E47) bind in a sequence=specific manner to the E-box motif (CANNTG), a cis-acting regulatory element found in a variety of eukaryotic transcription enhancers. Despite mounting evidence that TAL1 functions as a transcription factor upon ectopic expression in T-ALL cells, subordinate genes subject to transcriptional regulation by TAL1 have not as yet been identified. Therefore, the whole genome PCR approach will be used to isolate genomic DNA fragments with TAL1-binding specificity; these fragments should represent regulatory segments of genes whose expression may be subordinate to TAL1. In addition, differential display will be used to directly isolate cDNA sequences from genes regulated by TAL1. These investigations should provide insight into the role of ectopic TAL1 expression in the leukemogenic process of T-ALL.
| Baer, R; Hwang, L Y; Bash, R O (1997) Transcription factors of the bHLH and LIM families: synergistic mediators of T cell acute leukemia? Curr Top Microbiol Immunol 220:55-65 |
