In the past five years we have identified the developmental stage of Tcell differentiation at which malignant transformation caused by retroviral insertion of a vector containing ICN 1 becomes first apparent as the CD4-8+TCRalpha /beta minus stage that follows pre-TCR signaling. Consequently, the tumors are monoclonal with regard to TCR beta rearrangement but express diverse TCRalpha chains. The tumors exhibit a normal karyotype and genomic stability (verified by SKY and CGH),but are characterized by dysregulated expression of oncogenes and genes regulating survival and proliferation. Since sequencing has not revealed genetic instability and malignant cells can be detected early, 2-3 weeks after retroviral transduction , we will focus on insertional mutagenesis by the retroviral vector as a synergizing event since ICN1 overexpression alone does not result in tumors but in polyclonal, non-tumorigenic cells with slightly increased survival and proliferation when compared to phenotypically identical normal cells. We also established tht tumors exhibit an abnormal pattern of miRNA expression. We therefore will address the hypothesis that insertional mutagenesis and abnormally expressed miRNA contribute to the malignancy and will attempt to interfere with malignant growth by using antagomirs and mimics of miRNA and by knocking down abnormally overexpressed genes that are implicated in malignant growth.
AIMI : Determine integration sites of retroviral vector in tumor and non-malignant ICN1 overexpressing cells to analyze contribution of insertional mutagenesis to tumor development.
AIM2 : Epigenetic analysis of T-ALL versus phenotypically similar but normal or ICN1 overexpressing nontumorigenic cells.
AIM3 : Contribution of miRNA to malignant transformation.
AIM 4 : Sh RNA mediated knockdown of genes specifically overexpressed in T-ALL and overexpression of genes specifically repressed in tumors.

Public Health Relevance

Acute T lymphoblastic leukemia (T-ALL) continues to pose severe problems for disease management. The analysis of molecular and cellular pathways in the development of T-ALL will provide new clues about the initiation of the disease in murine models and thereby provide information of how it is related to mouse T cell development. Furthermore, the comparative analysis of genetic dysregulation in murine and human T-ALL will provide detailed insight into molecular targets for drug therapy. In fact, the relevance of such targets will be verified by in vivo analysis of tumor progression using modified murine T-ALL.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Dana-Farber Cancer Institute
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