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Departments of Pediatric Hematology/Oncology [A. B., M. B. D., A. L. Y.] and Medicine [T. N.], University of California, and The Scripps Research Institute [J. C. Y.], San Diego, California 92103-8447; Stanford University, Palo Alto, California 94304 [M. P. L.]; and University of Mississippi, Jackson, Mississippi 39216 [J. P.]
Frequent deletion of chromosome 9p21 in many cancers has suggested the presence of tumor suppressor genes in this region. Two genes mapping to 9p21, p15 and p16, encode inhibitors for cyclin-dependent kinases 4 and 6. We recently found that in T-cell acute lymphoblastic leukemia (T-ALL), both the p15 and p16 genes are deleted at a high frequency, with p16 gene deletion occurring slightly more frequently than p15 gene deletion. We now show that in addition to deletion, the p15 gene is preferentially hypermethylated at a 5' CpG island, which has been shown previously to be associated with loss of transcription of this gene. The p15 gene was methylated in 38% (17 of 45) of T-ALL patients at diagnosis and in 22% (7 of 32) of patients at relapse. On the other hand, methylation of the p16 gene was a rare event, occurring in 4% (2 of 49) of patients at diagnosis and in none (0 of 30) at relapse. The overall rates of alteration occurring in at least one allele of the p15 gene is 84% at diagnosis and 88% at relapse. These rates are as high as, if not greater than, those for the p16 gene (80% at diagnosis and 74% at relapse). In fact, such alterations involve both alleles in the majority of samples: 76% for p15 and 67% for p16 at diagnosis. All together, more than one-half (56%) of T-ALL samples harbor alterations in both alleles of both p15 and p16. These results lend strong support for a role of both p15 and p16 as tumor suppressors in T-ALL.
1 This work is supported by Grants R21 CA 70397, U10CA28439 from the National Cancer Institute, and FDA 001129 (to A. L. Y.), DK 49888 from NIH (to J. Y.), and U01 CA 64976 from the National Cancer Institute (to T. N.), and in part by NIH Grant M01 RR00827 from the General Clinical Research Center program. A. B. is supported by NIH Grant 2T32-HL07107 for training and research on blood and blood disease.
2 To whom requests for reprints should be addressed, at Department of Pediatric Hematology/Oncology, University of California San Diego Medical Center, 200 West Arbor Drive, San Diego, CA 92103-8447. Phone: (619) 543-6844; Fax: (619) 543-5413; E-mail: alyu@ucsd.edu.
Received 10/28/96. Accepted 1/18/97.
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