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Hypermethylation-associated Inactivation Indicates a Tumor Suppressor Role for p15^INK4B1

The Oncology Center [J. G. H., J. J., S. B. B.] and Departments of Otolaryngology [A. M.] and Medicine [S. B. B.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

The recently identified cyclin-dependent kinase inhibitor p15^INK4B is localized to a region on chromosome 9p21 frequently deleted in human tumors. Previous evidence has pointed to a related gene, p16^INK4A, as the principal target of this deletion. We report that in gliomas and, to a striking degree, in leukemias, the p15 gene is commonly inactivated in association with promoter region hypermethylation involving multiple sites in a 5'-CpG island. In some gliomas and all of the primary leukemias, this event occurs without alteration of the adjacent gene, p16^INK4A. In other tumors, including lung, head and neck, breast, prostate, and colon cancer, inactivation of p16^INK4B occurs only rarely and only with concomitant inactivation of p16. Aberrant methylation of p15^INK4B is associated with transcriptional loss of this gene. Treatment with the demethylating agent 5-aza-2'-deoxycytidine leads to re-expression of p15 mRNA. In selected leukemia cell lines, p15 inactivation correlates with known resistance to the growth-suppressive effects of transforming growth factor-ß. These results suggest that p15^INK4B is inactivated selectively in leukemias and gliomas and seems to constitute an important tumor suppressor gene loss in these neoplasms.

¹ This work was supported by NIH Grants CA-43318 and CA-58184. A. M. is a recipient of a Schweizensche Stiftung fur Medizinish-Biologische stipend.

² To whom requests for reprints should be addressed, at The Oncology Center, The Johns Hopkins University School of Medicine, 424 North Bond Street, Baltimore, MD 21231.

³ Present address: Neurochir. Universitat Klinik, Spitalstrasse 21, CH-4031 Basel, Switzerland.

Received 11/28/95. Accepted 12/29/95.

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				J. N. Rich, M. Zhang, M. B. Datto, D. D. Bigner, and X.-F. Wang Transforming Growth Factor-beta -mediated p15INK4B Induction and Growth Inhibition in Astrocytes Is SMAD3-dependent and a Pathway Prominently Altered in Human Glioma Cell Lines J. Biol. Chem., December 3, 1999; 274(49): 35053 - 35058. [Abstract] [Full Text] [PDF]

				C. M. Bender, M. L. Gonzalgo, F. A. Gonzales, C. T. Nguyen, K. D. Robertson, and P. A. Jones Roles of Cell Division and Gene Transcription in the Methylation of CpG Islands Mol. Cell. Biol., October 1, 1999; 19(10): 6690 - 6698. [Abstract] [Full Text] [PDF]

				S. Kitazawa, R. Kitazawa, and S. Maeda Transcriptional Regulation of Rat Cyclin D1 Gene by CpG Methylation Status in Promoter Region J. Biol. Chem., October 1, 1999; 274(40): 28787 - 28793. [Abstract] [Full Text] [PDF]

				E. E. Cameron, S. B. Baylin, and J. G. Herman p15INK4B CpG Island Methylation in Primary Acute Leukemia Is Heterogeneous and Suggests Density as a Critical Factor for Transcriptional Silencing Blood, October 1, 1999; 94(7): 2445 - 2451. [Abstract] [Full Text] [PDF]

				I. P. de Castro, M. Malumbres, J. Santos, A. Pellicer, and J. Fernandez-Piqueras Cooperative alterations of Rb pathway regulators in mouse primary T cell lymphomas Carcinogenesis, September 1, 1999; 20(9): 1675 - 1682. [Abstract] [Full Text] [PDF]

				A. S. Baur, P. Shaw, N. Burri, F. Delacretaz, F. T. Bosman, and P. Chaubert Frequent Methylation Silencing of p15INK4b (MTS2) and p16INK4a (MTS1) in B-Cell and T-Cell Lymphomas Blood, September 1, 1999; 94(5): 1773 - 1781. [Abstract] [Full Text] [PDF]

				J. R. Melki, P. C. Vincent, and S. J. Clark Concurrent DNA Hypermethylation of Multiple Genes in Acute Myeloid Leukemia Cancer Res., August 1, 1999; 59(15): 3730 - 3740. [Abstract] [Full Text] [PDF]

				L. Yuan, J. Shan, D. De Risi, J. Broome, J. Lovecchio, D. Gal, V. Vinciguerra, and H.-p. Xu Isolation of a Novel Gene, TSP50, by a Hypomethylated DNA Fragment in Human Breast Cancer Cancer Res., July 1, 1999; 59(13): 3215 - 3221. [Abstract] [Full Text] [PDF]

				A. Sgambato, M. Migaldi, B. Faraglia, L. Garagnani, G. Romano, C. De Gaetani, P. Ferrari, G. Capelli, G. P. Trentini, and A. Cittadini Loss of P27Kip1 Expression Correlates with Tumor Grade and with Reduced Disease-free Survival in Primary Superficial Bladder Cancers Cancer Res., July 1, 1999; 59(13): 3245 - 3250. [Abstract] [Full Text] [PDF]

				L. E. Lantry, Z. Zhang, K. A. Crist, Y. Wang, G. J. Kelloff, R. A. Lubet, and M. You 5-Aza-2'-deoxycytidine is chemopreventive in a 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone-induced primary mouse lung tumor model Carcinogenesis, February 1, 1999; 20(2): 343 - 346. [Abstract] [Full Text] [PDF]

				E. P. Xing, Y. Nie, L.-D. Wang, G.-Y. Yang, and C. S. Yang Aberrant methylation of p16INK4a and deletion of p15INK4b are frequent events in human esophageal cancer in Linxian, China Carcinogenesis, January 1, 1999; 20(1): 77 - 84. [Abstract] [Full Text] [PDF]

				S. J. Kuerbitz, J. Malandro, N. Compitello, S. B. Baylin, and J. R. Graff Deletion of p16INK4A/CDKN2 and p15INK4B in Human Somatic Cell Hybrids and Hybrid-derived Tumors Cell Growth Differ., January 1, 1999; 10(1): 27 - 33. [Abstract] [Full Text]

				X. Qian, L. Jin, E. Kulig, and R. V. Lloyd DNA Methylation Regulates p27Kip1 Expression in Rodent Pituitary Cell Lines Am. J. Pathol., November 1, 1998; 153(5): 1475 - 1482. [Abstract] [Full Text] [PDF]

				J. A. Mikovits, H. A. Young, P. Vertino, J.-P. J. Issa, P. M. Pitha, S. Turcoski-Corrales, D. D. Taub, C. L. Petrow, S. B. Baylin, and F. W. Ruscetti Infection with Human Immunodeficiency Virus Type 1 Upregulates DNA Methyltransferase, Resulting in De Novo Methylation of the Gamma Interferon (IFN-gamma ) Promoter and Subsequent Downregulation of IFN-gamma Production Mol. Cell. Biol., September 1, 1998; 18(9): 5166 - 5177. [Abstract] [Full Text]

				E. M. Swisher, D. G. Mutch, T. J. Herzog, J. S. Rader, L. D. Kowalski, A. Elbendary, and P. J. Goodfellow Analysis of MSH3 in Endometrial Cancers With Defective DNA Mismatch Repair Reproductive Sciences, July 1, 1998; 5(4): 210 - 216. [Abstract] [PDF]

				S. Faderl, H. M. Kantarjian, M. Talpaz, and Z. Estrov Clinical Significance of Cytogenetic Abnormalities in Adult Acute Lymphoblastic Leukemia Blood, June 1, 1998; 91(11): 3995 - 4019. [Full Text] [PDF]

				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]

				S. A. Foster, D. J. Wong, M. T. Barrett, and D. A. Galloway Inactivation of p16 in Human Mammary Epithelial Cells by CpG Island Methylation Mol. Cell. Biol., April 1, 1998; 18(4): 1793 - 1801. [Abstract] [Full Text]

				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]

				G. I. Shapiro, C. D. Edwards, M. E. Ewen, and B. J. Rollins p16INK4A Participates in a G1 Arrest Checkpoint in Response to DNA Damage Mol. Cell. Biol., January 1, 1998; 18(1): 378 - 387. [Abstract] [Full Text]

				J. R. Graff, J. G. Herman, S. Myohanen, S. B. Baylin, and P. M. Vertino Mapping Patterns of CpG Island Methylation in Normal and Neoplastic Cells Implicates Both Upstream and Downstream Regions in de Novo Methylation J. Biol. Chem., August 29, 1997; 272(35): 22322 - 22329. [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]

				M.H.L. Ng, Y.F. Chung, K.W. Lo, N.W.R. Wickham, J.C.K. Lee, and D.P. Huang Frequent Hypermethylation of p16 and p15 Genes in Multiple Myeloma Blood, April 1, 1997; 89(7): 2500 - 2506. [Abstract] [Full Text] [PDF]