GENETICS OF HEMATOPOIETIC CANCERS

Project: Research project

Project Details

Description

The long-term objectives are to define molecular mechanisms by which
specific translocations lead to apparent transcriptional activation of the
cellular proto-oncogenes in Burkitt's lymphoma (BL), an undifferentiated
B-lymphocyte cancer of man, and other hematopoietic cancers. The mechanism
of c-myc activation will be examined initially by: (1)\molecular cloning
and characterization of the Ramos BL c-myc alleles; (2)\characterization of
the c-myc transcript; and (3)\transfection of molecular clones of c-myc
into B-lymphoid cells to study the expression of the transferred c-myc
genes. A recombinant DNA library will be constructed and phage clones
containing c-myc gene will be identified by in situ hybridization screening
of plaques. Cloned c-myc genes will be characterized to identify key
structural differences between the normal and rearranged alleles that might
be related to their functional differences. The structure of the c-myc
transcripts will be examined by Northern blotting and S 1 nuclease mapping
techniques. These studies will test the hypothesis that the effects of
c-myc in Ramos BL is due to overexpression of a normal c-myc transcript
(gene dosage model of malignancy). Finally, to detect the possible
presence of a transcriptional enhancer sequence adjacent to the rearranged
Ramos c-myc allele, the isolated c-myc alleles will be cloned into the
shuttle vector pSV2-neo. These constructs will be transfected into NIH 3T3
cells and B-lymphoblastoid cell lines to detect differences in expression
and regulation between the normal and rearranged c-myc allele responsible
for enhanced expression. Transfection studies might also reveal
differences in the ability of fibroblasts versus lymphoid cells to detect
certain classes of activated proto-oncogenes. Although BL responds to
chemotherapy, early clinical relapse after remission is often characterized
by resistance to further therapy and a poor prognosis. Illumination of
mechanisms of enhanced expression of c-myc in BL and its biological role in
the genesis of this lymphoma might suggest whether this pathway is a
potential target for experimental intervention. Results from these studies
may be relevant to other proto-oncogenes structurally and functionally
related to c-myc, and thus to other cancers in which aberrant expression of
these genes might have a role in the genesis or maintenance of the
malignant phenotype. (X)
StatusFinished
Effective start/end date6/15/8411/30/87

Funding

  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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