Project Details


DESCRIPTION: (Applicant's Abstract) 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
Effective start/end date7/1/964/30/01


  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute


  • Genetics
  • Dermatology


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