Tumorigenic effects of Tax
Principal Investigator: Lee Ratner, MD, PhD, Washington University
T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell
leukemia lymphoma (ATLL). ATLL cells are characterized by constitutive NFκB
activation, a key feature of other lymphomas, myeloma, and solid tumors. The
proposed research program uses a physiologically relevant lymphoma model
associated with HTLV-1. Our primary hypothesis is that Tax activation of NFκB
is critical for tumorigenesis, particularly the alternative (alt) NFκB pathway.
Our goal is to test this hypothesis, and identify and characterize
Tax-interactive proteins that mediate alt NFκB activation. Two Specific Aims
Aim 1: To assess the role of
alt NFκB activity in Tax-mediated transformation.
A new humanized mouse model
is used for HTLV-1 infection and lymphoma development. We will use viral
variants expressing Tax mutants with defects in activating the alternative NFκB
pathway or both NFκB pathways, in order to define their role in disease
pathogenesis. A novel high-throughput viral integration assay is used to
monitor clonality of infected cells in these experiments.
Aim 2: To identify and
characterize Tax interactive proteins that mediate alt NFκB activation
We will identify Tax
interactive proteins that mediate alt NFκB pathway activation. Proteins that
interact with wild type but not mutant Tax will then be characterized using
shRNAs to assess their effect on Tax induced cleavage of alt NFκB precursor
protein, p100, as well as effects on proliferation and apoptosis of HTLV-1
transformed cells in culture and immunodeficient mice.
is expected that the information these physiologically relevant mouse models will
identify key target genes that may be inhibited in therapeutic trials of ATLL
or other lymphomas.