The current proposal builds upon studies initiated in the previous project period that utilized biolumine- scent imaging (BLI) to assess the biology and treatment of HTLV-1 Tax lymphomas. A tumor transplant model and a transgenic mouse model were established for imaging to assess tumor cell proliferation and dissemination. Understanding the pathogenesis of HTLV-1 Tax lymphomas, through NFKB activation, has direct relevance to a wide range of hematopoietic neoplasms that also utilize NFKB activation.
The aims are:
Aim 1. Use of high throughput screen to identify kinases that are critical for Tax-mediatedlymphoma cell proliferation and/or survival. We will use a Tax transgenic tumor cell line for to screen the siRNA library to the human kinome to uncover new information about the transformation pathways exploited by HTLV-1.
Aim 2. Use of BLI to assess the role of critical mediators of Tax tumorigenesis in a tumor transplant model. Tumor cell lines expressing luciferase will be infected with a lentivirus expressing siRNAto a possible mediator of Tax activity. Mediators of Tax activityto be investigated include components of the NFKB pathway, upstream activators, and downstream NFKB targets. Critical kinase mediators, identified from Aim 1, will also be validated using a model with fresh tumor transplants. The cell lines are screened for high levels of luciferase activity, and injected subcutaneously into Rag1 mice. Mice are imaged every 2-4 wks over 12-16 wks with or without treatment with specific small molecule inhibitors, and tumors are then analyzed by immunohistochemistry for Tax and luciferase, as well as markers of cell proliferation (BUDR incorporation), angiogenesis (CD31 expression), and apoptosis (Tunel stain).
Aim 3. Use of BLI to assess the role of critical mediators of Tax tumorigenesis in a transgenic mouse model. This mouse model includes Tax and LTR-luciferase transgenes. These mice will be bred with mice with conditional or non-conditional homozygous deletions of genes expressing critical mediators of tumorigenesis, including tumor suppressor Arf, NFKB subunits p50 and p52, and kinases identified in Aim 1. Tumors will be evaluated by bioluminescent imaging, pathology, IHC for Tax and luciferase, FACSfor FcvRII/lll, CD4, or CD8, and markers of proliferation, angiogenesis, and apoptosis.
Aim 4. Use of BLI and CGH to assess the role of genetic instability in Tax tumorigenesis. The role of genetic instability in tumor initiation, maintenance, or progression will be evaluated in Tax transgenic animals that also express the CDC25A protein fused to click beetle red. These findings will be correlated to mouse comparative genomic hybridization (CGH) arrays.
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