TLE1 Tumor Suppressor as a Key Regulator of myc Induced Leukemia
Research in pediatric cancer over last 30 years has led to improvements in the treatment and cure rate for most of the pediatric cancer. Despite improvement in the pediatric patient survival over the last decades, still about 30-40% of children die of cancer and also many treatments affects the quality of the life. There is a need for identification of new targets and anti-cancer agents to improve the survival and quality of life. TLE1 gene is a novel tumor suppressor and co-repressor gene that is deleted or methylated in acute myeloid leukemia (AML) and other hematological malignancies. TLE1 is capable of repressing many potential oncogenic pathways such as Notch, Myc, Wnt, and NFKB, but it is unclear which of these interactions are important in leukemogenesis. Myc is a master transcription regulator gene deregulated in many pediatric cancers including AML, ALL and neuroblastoma. Our preliminary studies indicate that loss of Tle1 cooperates with N-Myc to accelerate leukemia development in mice. We propose to determine how Tle1 modulates the N-Myc induced myeloid leukemia in mice and whether the homologous Groucho protein is able to regulate c-myc induced T-cell ALL in zebra fish. We plan to identify critical myc pathways and targets modulated by Tle1 in these models. Our long term goal is to use this information to design novel targeted therapies extendable to other myc driven pediatric cancers including neuroblastoma and lymphoma to effectively treat these childhood cancer.