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 #
5P01CA109901-08
Application #
8376650
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$203,515
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Lobbardi, Riadh; Pinder, Jordan; Martinez-Pastor, Barbara et al. (2017) TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia. Cancer Discov 7:1336-1353
Rahman, Sunniyat; Magnussen, Michael; León, Theresa E et al. (2017) Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia. Blood 129:3221-3226
Winter, Georg E; Mayer, Andreas; Buckley, Dennis L et al. (2017) BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment. Mol Cell 67:5-18.e19
Li, Z; Abraham, B J; Berezovskaya, A et al. (2017) APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL. Leukemia 31:2057-2064
Abraham, Brian J; Hnisz, Denes; Weintraub, Abraham S et al. (2017) Small genomic insertions form enhancers that misregulate oncogenes. Nat Commun 8:14385
Erb, Michael A; Scott, Thomas G; Li, Bin E et al. (2017) Transcription control by the ENL YEATS domain in acute leukaemia. Nature 543:270-274
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 351:1454-1458
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

Showing the most recent 10 out of 62 publications