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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA109901-09
Application #
8454435
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2013
Total Cost
$189,839
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Zhang, Tinghu; Kwiatkowski, Nicholas; Olson, Calla M et al. (2016) Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol 12:876-84
Hnisz, Denes; Weintraub, Abraham S; Day, Daniel S et al. (2016) Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351:1454-8
Akahane, K; Sanda, T; Mansour, M R et al. (2016) HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia. Leukemia 30:219-28
Tan, S H; Yam, A W Y; Lawton, L N et al. (2016) TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia 30:959-62
Frock, Richard L; Hu, Jiazhi; Meyers, Robin M et al. (2015) Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 33:179-86
Jiang, Wenxia; Lee, Brian J; Li, Chen et al. (2015) Aberrant TCRδ rearrangement underlies the T-cell lymphocytopenia and t(12;14) translocation associated with ATM deficiency. Blood 125:2665-8
Mansour, Marc R; Reed, Casie; Eisenberg, Amy R et al. (2015) Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia. Br J Haematol 168:230-8
Oldridge, Derek A; Wood, Andrew C; Weichert-Leahey, Nina et al. (2015) Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature 528:418-21
Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-20
Chipumuro, Edmond; Marco, Eugenio; Christensen, Camilla L et al. (2014) CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159:1126-39

Showing the most recent 10 out of 58 publications