Our laboratory is dedicated to the study of B cell neoplasms, particularly those containing chromosomal translocations (Tx) which interrupt the c-MYC/PVT 1 region on human chromosome 8 or mouse chromosome 15. This Tx interrupts the transcription of either c-Myc or Pvt 1 and is the principal lesion in many B cell malignancies including Burkitt's lymphoma (BL), AIDs-NHL, mouse plasmacytoma (PCT) and in some cases, Multiple Myeloma (MM). There is a restriction associated with this Tx such that only the immunoglobulin (Ig) heavy chain gene is found juxtaposed to c-Myc and only the Ig light chain gene is found juxtaposed to Pvt 1. Over the past several years, our laboratory has elucidated the structure of the mouse Pvt 1 locus as a step in understanding the relationship between these two vastly divergeant Txs which lead to such similar disease phenotypes. In the mouse model, we have identified a consistent Pvt 1/Ig Ck fusion product which is uniformly found in all tumors harboring Pvt 1 associated chromosomal Txs. Transgenic mice containing Pvt1/Ck and knockout mice defective in the expression of Pvt 1 have now been constructed to determine what role Pvt 1 serves in tumor progression as well as in normal development of the mouse. To identify the human analog of Pvt 1, we have looked for DNA rearrangements in samples from patients with MM and BL using DNA probes that span the entire region between human c-MYC and PVT. During the course of this study, we recently detected a length variation polymorphism in the region of PVT and studies are currently in progress among BL, AIDS-NHL and normal populations to determine which alleles may be more frequently associated with susceptibility to MYC/PVT Txs. Furthermore, we have now isolated PVT cDNA clones from peripheral blood that are alternatively spliced, contain multiple exons that span more than 300kb of the PVT locus, and which contain regions homologous to the mouse Pvt 1 gene. Future studies will be aimed at determining how PVT and c-MYC interact. Finally, in a search for c-Myc/Pvt 1 cooperating genes, we have examined p107, p21(Waf1), p53 and p73 for co-involvement in B cell tumorigenicity. In a more directed approach, we have also adopted spectral karyotyping (SKY) as a means of identifying subtle, yet nonrandom Txs in BL and AIDS-NHL which are not directly associated with c-MYC or PVT, but which might contribute to the malignancy pathway. To study these cytogenetic lesions, we have developed and modified chromosomal microdissection techniques that permit detailed examination of a single allele/chromosome at the DNA level.
| 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 |
