The NF-kB/Rel family of transcription factors play critical roles in the normal growth and differentiation of lymphoid cells. NF-kB/Rel proteins are required for normal differentiation of B-cells and play a critical role in T-cell activation. Upon T-cell activation, NF-kB proteins are translocated to the nucleus where they induce transcription of genes important for T-cell activation and proliferation. Alterations in the function of NF-kB and IkB proteins have been observed in a number of lymphoid malignancies. The applicant has recently identified frequent rearrangements of the NF-kB/Rel family of transcription factors in cell lines and tumor DNA derived from patients with cutaneous T-cell lymphomas (CTCLs). Approximately 20% of CTCL patient tumor DNA samples contain alterations in the nfkb-2 gene and rearrangement of this gene was also identified in the HUT 78 CTCL line. Nfkb-2 normally encodes a p100 precursor protein, which is proteolytically-cleaved to generate the mature p52 nfkb-2 protein. In HUT 78 cells, nfkb-2 gene rearrangement results in generation of a truncated p80 precursor protein (p80HT) as well as the mature p52 protein. Nfkb-2 rearrangement is also associated with overexpression of nfkb-2 RNA and proteins, and with high constitutive levels of nuclear nfkb-2 proteins. The overall goals of this project are to characterize the mechanisms by which nfkb-2 gene rearrangements may contribute to the genesis of T-cell lymphomas.
The Specific Aims of this application are: (1) to further characterize nfkb-2 gene alterations in tumor DNA from CTCL patients, to attempt to identify additional alterations in this gene in patients that do not exhibit gross genetic alterations, and to attempt to correlate nfkb-2 gene alterations with the clinical course of CTCL; (2) to characterize the biochemical properties (DNA binding, dimerization, transcriptional regulatory properties, and phosphorylation) of the p80HT nfkb-2 protein, to determine if alterations in these properties may contribute to the genesis of CTCL; (3) to study the regulatory control of the transcriptional promoter of the nfkb-2 gene, and determine the basis of the high levels of nfkb-2 transcription in HUT 78 cells, which may in turn contribute to lymphomagenesis; and (4) to assess the biological activities of truncated nfkb-2 genes in in vitro and in vivo systems, to attempt to understand the basis by which this rearrangement may lead to lymphomagenesis.
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