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.
| Bhaskara, Srividya; Knutson, Sarah K; Jiang, Guochun et al. (2010) Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18:436-47 |
| Knutson, Sarah K; Chyla, Brenda J; Amann, Joseph M et al. (2008) Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J 27:1017-28 |
| Bhaskara, Srividya; Chyla, Brenda J; Amann, Joseph M et al. (2008) Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell 30:61-72 |
| Hanson, Caroline A; Wood, Lauren D; Hiebert, Scott W (2008) Cellular stress triggers TEL nuclear export via two genetically separable pathways. J Cell Biochem 104:488-98 |
| Reed-Inderbitzin, E; Moreno-Miralles, I; Vanden-Eynden, S K et al. (2006) RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription. Oncogene 25:5777-86 |
| Amann, Joseph M; Chyla, Brenda J Irvin; Ellis, Tiffany C et al. (2005) Mtgr1 is a transcriptional corepressor that is required for maintenance of the secretory cell lineage in the small intestine. Mol Cell Biol 25:9576-85 |
| Moreno-Miralles, Isabel; Pan, Ling; Keates-Baleeiro, Jennifer et al. (2005) The inv(16) cooperates with ARF haploinsufficiency to induce acute myeloid leukemia. J Biol Chem 280:40097-103 |
| Yang, Genyan; Khalaf, Waleed; van de Locht, Louis et al. (2005) Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein. Mol Cell Biol 25:5869-79 |
| Linggi, Bryan E; Brandt, Stephen J; Sun, Zu-Wen et al. (2005) Translating the histone code into leukemia. J Cell Biochem 96:938-50 |
| Durst, Kristie L; Lutterbach, Bart; Kummalue, Tanawan et al. (2003) The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain. Mol Cell Biol 23:607-19 |
Showing the most recent 10 out of 27 publications
