The applicant and others have shown recurring deletions of 9p in acute lymphoblastic leukemias, gliomas and lung cancers suggesting that a tumor suppressor gene(s) (TSG) is likely to be located in this region. One proposed candidate gene is CDKN2 (pl6""""""""'IMTS1). This gene is an attractive candidate for a TSG because loss of its normal function as an inhibitor of CDKN4, a cyclin dependent kinase could lead to uncontrolled cell growth. Inactivation of CDN2 by homozygous deletion or point mutation has been reported in a large proportion of cultured cell lines from multiple tumor types. Mutations in CDKN2 occur with less frequency in primary tumors. However, germline point mutations in this gene have recently been described in familial melanoma. Proof that CDKN2 is the 9p tumor suppressor gene that is involved in all tumors with 9p abnormalities awaits demonstration of its ability to suppress tumorigenicity when introduced into cell lines with deletions. However, there is mounting evidence that CDKN2 may not be the only biologically relevant gene in this region. The applicant has cloned the MTAP gene and other transcription units in the critical region on 9p2l. The overall goal of this proposal is to characterize the region of the tumor suppressor locus on 9p and to determine whether there are other TSGs involved.
The specific aims are: 1) to identify transcription units in the critical region and to test for alterations of such transcripts in glioma cell lines and in primary tumors. 2) to obtain full length clones of any relevant transcripts from cDNA libraries. Further characterization of the genes will include sequencing, analysis of the predicted function of the protein, and mapping of its genomic structure. 3) to reintroduce identified candidate TSGs from 9p2l-22 into mouse and human cell lines with deletions by minigene or YAC transfection.4) to search for possible clues as to the mechanism of the deletions. 5) to determine the clinical significance of loss of candidate TSGs in gliomas.
| Gao, Q; Horwitz, M; Roulston, D et al. (2000) Susceptibility gene for familial acute myeloid leukemia associated with loss of 5q and/or 7q is not localized on the commonly deleted portion of 5q. Genes Chromosomes Cancer 28:164-72 |
