The overall goals of this research proposal are to understand the mechanisms of tumor suppression by the p27kip1 protein in hematopoietic malignancies. P27 is a cyclin-dependent kinase inhibitor that negatively regulates cell division. P27 functions as a tumor suppressor in mice and loss of p27 expression is a common event in human malignancies including lymphoid and myeloid hematopoietic cancers. In order to characterize pathways that cooperate with p27-loss during the development of hematopoietic cancer, we have used insertional mutagenesis in mice to identify a defined set of genomic loci that are likely to harbor oncogenes that collaborate with reduced p27 expression. I now propose to develop in vivo murine models to examine the biologic activities of these putative novel oncogenes within hematopoietic cells, and to determine if they cooperate with p27-loss during the development of lymphomas and leukemias. These studies may lead to mechanistic insights regarding the role of p27 in the development of hematopoietic cancers, as well as identify novel oncogenes that contribute to the genesis of leukemia and lymphoma. This information may also facilitate the development of new prognostic markers, as well as new treatment approaches, for human cancers that have reduced p27 expression. In this proposed program I will gain training in the area of in vivo modeling of cell cycle related hematolymphoid disease under the scientific mentorship of Dr. Bruce Clurman, an expert in cell cycle regulation, and the career mentorship of Dr. Mark Groudine, a leader in the study of transcriptional regulation. The training proposed in this project is also augmented by the involvement of a number of consultants, as well as an advisory committee, who are experts in the fields of hematopoiesis, cell cycle control, gene therapy, and oncogenes. In addition, the Fred Hutchinson Cancer Center provides an outstanding training environment for physician-scientists. This research program will provide the applicant with the training and mentoring required to develop an independent career in academic pathology focused on cell cycle-related disorders.
| Kuppers, Daniel A; Hwang, Harry C; Jackson, Aimee L et al. (2011) Effect of Xpcl1 activation and p27(Kip1) loss on gene expression in murine lymphoma. PLoS One 6:e14758 |
| Besson, Arnaud; Hwang, Harry C; Cicero, Samantha et al. (2007) Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev 21:1731-46 |
| Hwang, Harry C; Clurman, Bruce E (2005) Cyclin E in normal and neoplastic cell cycles. Oncogene 24:2776-86 |
| MacAlpine, D M; Kolesar, J; Okamoto, K et al. (2001) Replication and preferential inheritance of hypersuppressive petite mitochondrial DNA. EMBO J 20:1807-17 |
