Jason T. Yustein, M.D., Ph.D.
M.D./Ph.D.: Case Western Reserve University, Cleveland, Ohio
General Pediatrics Residency: Johns Hopkins University, Baltimore, MD
Pediatric Hematology-Oncology Fellowship: Johns Hopkins University/National Cancer Institute
Insights into Molecular Pathogenesis of Pediatric Sarcomas
Pediatric sarcomas compromise approximately 10-12% of all pediatric malignancies. Advancements in therapeutic interventions for these diseases have not been extremely successful, especially for those patients that present with metastatic disease, with long-term survival of less than 20%. Therefore it is essential that we improve our understanding of the biology and molecular pathogenesis of these extremely aggressive diseases in order to devise new therapeutic targets.
Our laboratory has several projects focusing on the biology and genetics of these tumors through the development of new model systems and investigating the functions of critical genetic components. One project is the development of a novel genetically engineered mouse model (GEMM) of metastatic osteosarcoma, which is the primary bone tumor in the pediatric population. We are utilizing cell-specific alterations of the tumor suppressor gene p53, in order to generate a novel model of metastatic osteosarcoma. The novel osteoblast-specific GEMM of metastatic osteosarcoma can recapitulate the natural endogenous formation of osteosarcomas with a high propensity for metastasis. This model will be extremely valuable towards gaining a better understanding of the genetic differences, including gene and microRNA expression, between localized and metastatic disease and provide a valuable representative model of osteosarcoma biology. In addition, we envision this system can be utilized as a pre-clinical model for therapeutic investigations of novel agents.
Our laboratory also has ongoing projects investigating the role of the oncogene c-Myc in Ewing sarcoma (EWS), the second most common bone tumor in the pediatric population. As a transcription factor, c-Myc regulates the expression of numerous critical genes involved in cellular growth, proliferation and metabolism. We know that most EWS express high levels of Myc and thus understanding the genes and microRNAs, and their subsequent biological roles can provide insights into key genetic events required for tumor development and progression.
Furthermore, we are interested in understanding the biological ramifications of exposure of sarcoma cells to hypoxic conditions. Tumor cells must adapt under these conditions in order to continue their growth and proliferation. Additional evidence suggests that malignant cells that are successful in this adaptation are often more aggressive, and metastatic, in nature.
Baylor College of Medicine
Feigin Center 1030.03
Houston, TX 77030
- Awad* O, Yustein* JT, Barber-Rotenberg J, Toretsky J, and Loeb D. High Aldehyde Dehydrogenase Activity Identifies a Chemotherapy-Resistant Population of Ewing’s Sarcoma Cells with a Stem Cell Phenotype that Retains Sensitivity to EWS-FLI1 Inhibition. Submitted, PLoS ONE. *Contributed equally to this manuscript.
- Yustein JT, Liu YC, Gao P, Jie C, Vuica-Ross M, Chng WJ, Eberhart CG, Bergsagel PL and Dang CV. (2010). Putative Ectopic Myc target genes in a Human B Cell Neoplastic Model: Induction of JAG2 by MYC Augments Hypoxic Growth and Tumorigenesis, PNAS, 107:3534-9.
- Yustein JT, Redham S, Bertuch AA, Goss JA, Brandt ML, Eldin K, Lu X and Hicks J. (2010). Abdominal Undifferentiated Small Round Cell Tumor with Unique Translocation (X;19)(q13;q13.3), Pediatric Blood and Cancer, 54:1041-4.
- Dang CV, Kim JW, Gao P and Yustein JT. (2008). Interplay between Myc and HIF in Cancer, Nat Rev Cancer, 8:51-6.
- Yustein JT and Dang CV. (2007). Update on Biology and Treatment of Burkitt Lymphoma, Curr Opin Hematol., 4, 375-81. Review.
- Zeller KI, Zhao XD, Lee CWH, Chin KP, Yustein JT, Ooi HS, Shahab A, Yong HC, Fu Y, Weng Z, Kuzuetsov VA, Sung WK, Ruan Y, Dang CV, Wei CL. (2006). Global Mapping of c-Myc Binding Sites and Target Gene Networks in Human B Cells, PNAS, 103: 17834-17839.
- Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA, Yustein JT, Kim JW, Yustein JT, Lee LA, and Dang CV. (2005). Myc stimulates nuclear encoded mitochondrial genes and mitochondrial biogenesis, Mol. Cell. Biol., 25: 6225-6234.
- Gwack Y, Nakamura H, Lee SH, Souvlis J, Yustein JT, Gygi S, Kung HJ, and Jung JU. (2003). Poly(ADP-ribose) polymerase 1 and Ste20-like kinase hKFC act as transcriptional repressors for gamma-2 herpesvirus lytic replication, Mol.Cell. Biol., 23: 8282-94.
- Yustein JT, Robinson D, Templeton D, and Kung HJ. (2003). The human subfamily of Ste20-like kinases that activates p38 selectively through MKK3 and are regulated via a PP2A-dependent mechanism, Oncogene, 22: 6129-41.
- Yustein JT, Li D, Robinson D and Kung HJ. (2000). KFC, a Ste20-like kinase with mitogenic potential and capability to activate the SAPK/JNK pathway, Oncogene, 19: 710-8.