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 336 amino acids of TEL, an ETS-family transcription factor, to the DNA binding and transactivation domains of AML-1, a transcription factor that is the target of multiple translocations in myeloid leukemia. Up to 90% of patients with the t(12;21), have also sustained inactivating 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. Our preliminary work defines corepressors that bind to TEL and/or AML-1 to mediate transcriptional repression of AML-1 target genes. This proposal tests the hypothesis that the inhibition of AML-1-regulated genes, including the p14ARF tumor suppressor that mediates the oncogene checkpoint, by the t(12;21) fusion protein is a key event in leukemogenesis.
Specific Aim 1 will define the molecular contacts between TEL/AML-1 and co-repressors, , histone deacetylases, and the histone methyltransferase Suv39h1 and define the mechanism of TEL/AML-1mediated repression at the molecular level.
Specific Aim 2 will define the contribution of each co-repressor contact to TEL/AML-1 function using the p14ARF tumor suppressor as an endogenous readout.
Aim 2 will also define the biological relevance of repression of p14ARF. We have determined that TEL inhibits the growth of Ras-transformed cells by altering cellular adhesion and inducing apoptosis.
In Specific Aim 3 we will determine how the loss of TEL cooperates with TEL/AML-1 to promote leukemia. The experiments proposed will define the molecular mechanism of repression by the t(12;21) and provide insights into how the t(12;21) results in the generation and maintenance of leukemia.
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