B cell malignancies such as Burkitts lymphoma (BL), AIDs-NHL, some Diffuse Large Cell B lymphomas (DLCL) and the mouse plasmacytoma (PCT) present with a characteristic non-random chromosomal translocation (Tx) that often results in the constitutive expression of c-MYC, an important regulator of cellular proliferation. The chromosomal breakpoint associated with these Txs can be found within a large region extending between 50kb 5 of c-MYC to 400kb 3 of c-MYC (in a region termed PVT) on human chromosome 8q24 (or mouse Chr15). Breakpoint clustering in the PVT region indicates the target of these Txs may be a gene(s) or c-Myc associated regulatory regions. To understand more about regulation of c-MYC expression, we have cloned and sequenced cDNAs corresponding to the PVT region, but to date, we are unable to discern any significant ORFs suggesting that the PVT RNAs may actually be non-coding and possibly regulatory in function. Hence, we propose that close proximity of transcriptionally active c-MYC and PVT genes may indicate co-regulated expression through shared enhancers and regulatory factors. We have now cloned large genomic segments of the human, mouse and zebrafish c-MYC/PVT region in a search for these putative shared enhancers. Particularly in view of the smaller intron size associated with zebrafish, we expect that conserved intron sequences found between species will represent prospective regulatory/enhancer candidates. Subsequent experiments will deploy these ?trapped? sequences in constructs designed to examine transcription of c-MYC and PVT. From a different approach to understanding c-MYC/PVT transcriptional control, we have initiated a study of allele specific expression of c-MYC/PVT using c-MYC allelic variants identified by our laboratory. The allelic variants were originally identified through a screening of large cohorts of normal healthy volunteers at the NIH Blood Bank by PCR-based SSCP analysis. The results of this study have revealed a c-MYC allele (CAA-33) that is exclusively African or African-American in origin. From a survey of African BL samples, we also find CAA-33 is significantly over- represented and unexpectedly, is never found as the translocated allele. This observation has lead us to propose that CAA-33 may be transcribed less efficiently, and therefore, is less susceptible to chromosomal breakage as found with Txs. Consistent with this hypothesis, we find lower levels of expression of the CAA-33 allele in peripheral blood of normal individuals suggesting CAA-33 may be lacking in enhancers. A second c-MYC allele (S11N) is found exclusively in Caucasian populations and shows no change in frequency when normal healthy and AIDS-NHL population cohorts are compared. In studies of c- MYC exon 3, we have found a third c-MYC variant allele (K288S) which is rare (<1/1000) in the US population and which is apparently silenced, presumably due to the absence of a regulatory element. Presently, these variant alleles are now undergoing intense studies in parallel with the search for enhancer/regulatory sequences described above for human, mouse and zebrafish. - Burkitt's lymphoma, c-myc, AIDS-NHL, PVT, - Human Subjects & Human Tissues, Fluids, Cells, etc. & Neither Human Subjects nor Human Tissues
| Lehrnbecher, T; Foster, C B; Zhu, S et al. (1999) Variant genotypes of the low-affinity Fcgamma receptors in two control populations and a review of low-affinity Fcgamma receptor polymorphisms in control and disease populations. Blood 94:4220-32 |
