Tobacco Documents Online

THE COUNCIL FOR TOBACCO RESEARCH-U.S.A., INC. Memorandum To: Dr. H.McAllister and Staff From: D.H.Ford Re: Site visit with Dr. Susan Astrin, Institute for Cancer Research, Fox Chase, July 8, 1992. Grant No.2480A Entitled "Deregulation of c-myc in colon carcinoma and AIDS lymphoma." Goal: To determine the molecular mechanism by which c-myc is:_-de-._ regulated in colon carcinoma cells and in B-HIV cells. Specific Aims: l.To determine if transcription is deregulated at the point of initiation of message or whether an elongation block at the exonl/intronl junction is relieved, 2. To determine the role of DNA binding proteins (histones possibly) in the regulation and deregulation of myc transcription,3. To reproduce regulated and :` deregulated transcription of c-myc in vitro, and 4. to determine the biological effects of deregulated myc loci. Results:Dr. Astrin has documented in her publications that deregulated expression of the c-myc proto-oncogene occurs in 2/3 of primary human colon carcinomas .:-and in colon carcinoma lines. c-myc RNA and protein was expressed at 10-40 times that observed in normal colon mucosa. Further, in human primary colon carcinoma samples she has observed a loss of heterozygosity in chromosome 5q (location of the adenomatous poluposis coli gene (APC). She has now transferred chromosome 5 from normal cells to each of 2 colon carcinoma cell lines (which expressed deregulated c-myc). These cell lines now expressed c-myc in a manner observed in normal cells. This would suggest that the gene/s suppressing c-myc are located on chromosome 5 and are lost in colon cancer. Thus, iE7one were to speculate as to the normal role of c-myc and its RNA/protein, one might conclude that it plays a normal role in the replacement of sloughed colon epithelial cells. This may be associated with an as"yet to be identified trans- cription factor which regulates cell movement into 'S' phase, and is thus important in regulating cell division and is normally suppressed. A second line of investigation relates to a subset of B cells which become malignant when infected with HIV-1. This line of cells contains both HIV and EBV genomes and expresses elevated levels of c-myc RNA and protein. Further, these cells exhibit evidence of a transformed phenotype ..as indicated by their growth inNsersun__and:'.in their ability to form colonies in soft agar as well as producing malignant tumors in severe combined immunodeficient (SCID) mice. Thus, her data demonstrates a relationship with B-cell lymphomas associated with HIV deregulation of c-myc and an increase in c-myc RNA and protein. Speculating in the course of our conversation, this relationship between the B-cell subset and HIV may play some role in the CNS lymphomas observed in the CNS in patients with advanced AIDS. Comment: An interesting program which appears to be expanding our understanding of mechanisms which prevent colon cancer (suppressor genes) or if deleted or mutated permit over expression of a gene (c-myc) which may normally play a role in maintaining the integrity of the colon mucosal lining. Her second research area of interest with B-cells suggest that B-cell lymphomas in AIDS result from a failure of suppression of c-myc, which may be of use in understanding other of the AIDS-related disorders. DHF