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Distinct Patterns of Inactivation of p15^INK4B and p16^INK4A Characterize the Major Types of Hematological Malignancies¹

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 p16^INK4A and p15^INK4B are frequent alterations in neoplasia, often resulting from homozygous deletion or promoter region hypermethylation. We have analyzed both modes of inactivation of p15^INK4B and p16^INK4A in the major types of adult and pediatric hematological malignancies. Hypermethylation of p15^INK4B, without alteration of p16^INK4A, 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 p15^INK4B nor p16^INK4A were inactivated in any stage of chronic myelogenous leukemia. Hypermethylation of p16^INK4A, often without alterations of p15^INK4B, 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 p15^INK4B and p16^INK4A 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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				B. Quesnel, G. Guillerm, R. Vereecque, E. Wattel, C. Preudhomme, F. Bauters, M. Vanrumbeke, and P. Fenaux Methylation of the p15INK4b Gene in Myelodysplastic Syndromes Is Frequent and Acquired During Disease Progression Blood, April 15, 1998; 91(8): 2985 - 2990. [Abstract] [Full Text] [PDF]

				U. Klangby, I. Okan, K. P. Magnusson, M. Wendland, P. Lind, and K. G. Wiman p16/INK4a and p15/INK4b Gene Methylation and Absence of p16/INK4a mRNA and Protein Expression in Burkitt's Lymphoma Blood, March 1, 1998; 91(5): 1680 - 1687. [Abstract] [Full Text] [PDF]

				B. Gardie, J.-M. Cayuela, S. Martini, and F. Sigaux Genomic Alterations of the p19ARF Encoding Exons in T-Cell Acute Lymphoblastic Leukemia Blood, February 1, 1998; 91(3): 1016 - 1020. [Abstract] [Full Text] [PDF]

				T. Uchida, T. Kinoshita, H. Nagai, Y. Nakahara, H. Saito, T. Hotta, and T. Murate Hypermethylation of the p15INK4B Gene in Myelodysplastic Syndromes Blood, August 15, 1997; 90(4): 1403 - 1409. [Abstract] [Full Text] [PDF]