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The Oncology Center [J. G. H., C. I. C., J-P. J. I., M. I. C., S. J. S., and S. B. B.] and Departments of Medicine [S. B. B.] and Pediatrics [C. I. C.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Inactivation of the cyclin-dependent kinase inhibitors p16INK4A and p15INK4B are frequent alterations in neoplasia, often resulting from homozygous deletion or promoter region hypermethylation. We have analyzed both modes of inactivation of p15INK4B and p16INK4A in the major types of adult and pediatric hematological malignancies. Hypermethylation of p15INK4B, without alteration of p16INK4A, was an almost universal finding in adult acute myelogenous leukemia, and occurred very frequently in adult acute lymphocytic leukemia and pediatric acute myelogenous leukemia and acute lymphocytic leukemia. In contrast, neither p15INK4B nor p16INK4A were inactivated in any stage of chronic myelogenous leukemia. Hypermethylation of p16INK4A, often without alterations of p15INK4B, was found in non-Hodgkin's lymphoma and was much more frequent in cases with high-grade than low-grade histology. Enriched normal bone marrow stem cells had no detectable promoter region methylation of these genes, as analyzed by a newly developed PCR method. Remarkably distinct patterns of inactivation of p15INK4B and p16INK4A characterize different types of hematological malignancy, and alterations in these tumor suppressor genes are one of the most common alterations in hematological malignancies.
1 Supported by Grant CA43318 and NIH Core Grant 2P30-CA06973-34. J. G. H. and S. B. B. receive research funding and are entitled to sales royalty from ONCOR, which is developing products related to research described in this paper. The terms of this arrangement have been reveiewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies.
2 To whom requests for reprints should be addressed, at The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231.
Received 11/ 4/96. Accepted 1/18/97.
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