The t(12;21) is the most frequent genetic abnormality associated with pediatric B-cell ALL, present in 25-30% of all cases. This translocation fuses the N-terminal 333 amino acids of TEL, a putative ets family transcription factor, to the DNA binding and transactivation domains of AML-lB, a transcription factor that is the target of multiple translocations in myeloid leukemia. Our preliminary work indicates that the addition of the N-terminal 3/4 of TEL to AML-lB converts AML-lB from an activator to a repressor of transcription. This proposal tests the hypothesis that the inhibition of AML- lB transcriptional activity by the t(12;21) fusion protein is a key event in leukemogenesis. Up to 90% of patients with the t(12;21), also have mutations in their second TEL allele. The high frequency of loss of TEL function suggests that TEL is a tumor suppressor and that its deletion cooperates with t( 12;21) in leukemogenesis.
Specific aim 1 will determine the molecular mechanism of TEL/AML- lB-mediated transcriptional regulation. These experiments will define both the mechanism of repression and the subdomains of TEL and AML-lB that bring about this repression. With this information, the factors that mediate these transcriptional effects can be identified.
Specific aim 2 will test the hypothesis that TEL is a tumor suppressor by determining whether its overexpression inhibits cellular proliferation both in vitro and in vivo.
In specific aim 3, transgenic mice will be engineered to inducibly express the t(12;21) fusion protein to examine whether TEL/AML-lB is a dominant interfering protein that induces leukemia, and whether its continuous expression is required to maintain the leukemic state. By crossing these mice with TEL-deficient mice, we will directly test whether the two lesions observed in the clinic cooperate in leukemogenesis. The experiments proposed will answer fundamental questions about the role of the t(12;21) in the generation and maintenance of leukemia and will provide a murine model for t 12;21 -associated leukemia.
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