Inactivation of the p15INK4B and p16INK4 Genes in Hematologic Malignancies

Leukemia and Lymphoma

Volumn 23, Issue 42067, 1996, Pages 235-245

  Heyman, Mats ^a   Einhorn, Stefan ^a  

^a KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

ALL; CDKN2; CDKN2B; leukemia; lymphoma; p15; p16

Indexed keywords

CELL PROTEIN; PROTEIN P15; PROTEIN P16; PROTEIN P53; UNCLASSIFIED DRUG; CARRIER PROTEIN; CDKN2B PROTEIN, HUMAN; CELL CYCLE PROTEIN; CYCLIN DEPENDENT KINASE INHIBITOR 2B; PROTEIN P16INK4A; TUMOR SUPPRESSOR PROTEIN;

CARCINOGENESIS; CELL CYCLE; CHROMOSOME 9P; GENE ACTIVITY; GENE FREQUENCY; GENE FUNCTION; GENE MAPPING; GENE MUTATION; HUMAN; HUMAN CELL; LEUKEMIA; LYMPHOMA; MAJOR CLINICAL STUDY; MOLECULAR GENETICS; PRIORITY JOURNAL; PROGNOSIS; REVIEW; SOLID TUMOR; TUMOR SUPPRESSOR GENE; BIOSYNTHESIS; BLOOD DISEASE; GENE EXPRESSION REGULATION; GENETICS; METABOLISM;

CARRIER PROTEINS; CELL CYCLE PROTEINS; CYCLIN-DEPENDENT KINASE INHIBITOR P15; CYCLIN-DEPENDENT KINASE INHIBITOR P16; GENE EXPRESSION REGULATION, NEOPLASTIC; HEMATOLOGIC NEOPLASMS; HUMANS; TUMOR SUPPRESSOR PROTEINS;

EID: 0030299866     PISSN: 10428194     EISSN: 10292403     Source Type: Journal    
DOI: 10.3109/10428199609054826     Document Type: Article

References (161)

1. Vogelslein B., Fearon E. R., Hamilton S. R., Kern S. E., Preisinger A. C., Leppert M., Nakamura Y., White R., Smits A. M., Bos J. L. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 1988; 319: 525 – 32
2. Klein G. Mechanisms of oncogene activation. Triangle 1991; 30: 73 – 80
3. Hunter T. Cooperation between oncogenes. Cell 1991; 64: 249 – 270
4. Marshall C. Tumor suppressor genes. Cell 1991; 64: 313 – 326
5. Cantley L. C., Auger K. R., Carpenter C., Duckworth B., Graziani A., Kapeller R., Soltoff S. Oncogenes and signal transduction. Cell 1991; 64: 281 – 302
6. Cross M., Dexter T. M. Growth factors in development, transformation, and tumorigenesis. Cell 1991; 64: 271 – 80
7. Sawyers C. L., Denny C. T., Witte O. N. Leukemia and the disruption of normal hematopoiesis. Cell 1991; 64: 337 – 50
8. Green D. R., Bissonette R. P., Cotter T. G. Apoptosis and cancer. Princip. Pract. Oncol. 1994; 8: 1 – 14
9. Shivdasani R. A., Mayer E. L., Orkin S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 1995; 373: 432 – 434
10. Warren A. J., Colledge W. H., Carlton M. B., Evans M. J., Smith A. J., Rabbins T. H. The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell 1994; 78: 45 – 57
11. Pui C.-H., Crist W. M., Look A. T. Biology and clinical significance of cytogenetic abnormalities in childhood acute lymphoblastic leukemia. Blood 1990; 76: 1149 – 1463
12. Warrell R. J., De T. H., Wang Z. Y., Degos L. Acute promyelocytic leukemia. N. Engl. J. Med. 1993; 329: 177 – 89
13. Campana D., Pui C.-H. Detection of minimal residual disease in acute leukemia: methodologic advances and clinical significance. Blood 1995; 85: 1416 – 1434
14. De Thé H., Lavau C., Marchio A., Chomienne C., Degos L., Dejean A. The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 1991; 66: 675 – 684
15. Cline M. J. The molecular basis of leukemia. N. Engl. J. Med. 1994; 330: 328 – 336
16. Lugo T. G., Pendergast A. M., Muller A. J., Witte O. N. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990; 247: 1079 – 82
17. Fletcher J. A., Tu N., Tantravahi R., Sallan S. E. Extremely poor prognosis of pediatric acute lymphoblastic leukemia with translocation (9;22): updated experience. Leukemia Lymphoma 1992; 8: 75 – 79
18. Arthur D. C., Bloomfield C. D., Lindquist L. L., Nesbit M. E., Jr. Translocation 4;11 in acute lymphoblastic leukemia: Clinical characteristics and prognostic significance. Blood 1982; 59: 96 – 99
19. Heerema N. A., Arthur D. C., Sather H., Albo V., Feusner J., Lange B. J., Steinherz P. G., Zeltzer P., Hammond D., Reaman G. H. Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia: impact of the 11q23 breakpoint on outcome: a report of the Childrens Cancer Group. Blood 1994; 83: 2274 – 84
20. Kowalczyk J., Sandberg A. A possible subgroup of ALL with 9p-. Cancer Genet Cytogenet. 1983; 9: 383 – 385
21. Chilcote R., Brown W., Rowley J. Lymphoblastic leukemia with lymphomatous features associated with abnormalities of the short arm of chromosome 9. N. Engl. J. Med. 1985; 313: 286 – 291
22. Heinonen K., Rautonen J., Siimes M. A., Knuutila S. Cytogenetic study of 105 children with acute lymphoblastic leukemia. Eur. J. Haematol. 1988; 41: 237 – 242
23. Murphy S., Raimondi S., Rivera G., Crone M., Dodge R., Behm G., Pui C.-H., Williams D. Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastci leukemia: Association with high-risk clinical features. Blood 1989; 74: 409 – 415
24. Heim S., BékÁssy A. N., Garwicz S., Heldrup J., Kristoffersson U., Mandahl N., Wiebe T., Mitelman F. Bone marrow karyotypes in 94 children with acute leukemia. Eur. J. Haematol. 1990; 44: 227 – 233
25. Pollak C., Hagemeijer A. Abnormalities of the short arm of chromosome 9 with partial loss of material in hematological disorders. Leukemia 1987; 1: 541 – 548
26. Carroll A., Castleberry R., Crist W. Lack of association between abnormalities of the chromosome 9 short arm and either “lymphomatous” features or T cell phenotype in childhood acute lymphocytic leukemia. Blood 1987; 69: 735 – 738
27. Olopade I. O., Jenkins R. B., Ransom D. T., Malik K., Pomykala H., Nobori T., Cowan J. M., Rowley J. D., Diaz M. O. Molecular analysis of deletions of the short arm of chromosome 9 in human gliomas. Cancer Res. 1992; 52: 2523 – 2529
28. Miyakoshi J., Dobler K. D., Allalunis-Turner J., McKean J. D. S., Petruk K., Allen P. B. R., Aronyk K. N., Weir B., Huyser-Wierenga D., Fulton D., Urtasun R. C., Day R. S., III. Absence of IFNA and IFNB genes from human malignant glioma cell lines and lack of correlation with cellular sensitivity to interferons. Cancer Res. 1990; 50: 278 – 283
29. Bello M. J., Moreno S., Rey J. A. Involvement of 9p in metastatic ovarian adenocarcinomas. Cancer Genet. Cytogenet. 1990; 45: 223 – 229
30. Bello M. J., Rey J. A. Chromosome aberrations in metastatic ovarian cancer: Relationship with abnormalities in primary tumors. Int. J. Cancer 1990; 45: 50 – 54
31. Lukeis R., Irving L., Garson M., Hasthorpe S. Cytogenetics of non-small cell lung cancer: Analysis of consistent non-random abnormalities. Genes, Chromosomes Cancer 1990; 2: 116 – 124
32. Cowan J. M., Halaban R., Francke U. Cytogenetic analysis of melanocytes from premalignant nevi and melanomas. J. Natl. Cancer Inst. 1988; 80: 1159 – 1164
33. Bale S. J., Dracopoli N. C. Chromosome 9p and hereditary cutaneous malignant melanoma. J. Natl. Cancer Inst. 1989; 81: 70
34. Cannon-Albright L. A., Goldgar D. E., Meyer L. J., Lewis C. M., Anderson D. E., Fountain J. W., Hegi M. E., Wiseman R. W., Petty E. M., Bale A. E., Olopade O. I., Diaz M. O., Kwiatkowski D. J., Piepkorn M. W., Jones J. J., Skolnick M. H. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22. Science 1992; 258: 1148 – 1152
35. Trent J. M., Olson S., Lawn R. M. Chromosomal localization of human leukocyte, fibroblast, and immune interferon genes by means of in situ hybridization. Proc. Natl. Acad. Sci. USA 1982; 79: 7809 – 7813
36. Diaz M., Ziemin S., Lebeau M., Pitha P., Smith S. D., Chilcote R. R., Rowley J. D. Homozygous deletion of the α- and β1-interferon genes in human leukemia and derived cell lines. Proc. Natl. Acad. Sci. USA 1988; 85: 5259 – 5263
37. Diaz M., Rubin C., Harden A., Ziemen S., Larson R., Le Beau M., Rowley J. Deletions of interferon genes in acute lymphoblastic leukemia. N. Engl. J. Med. 1990; 322: 77 – 82
38. Einhorn S., Grandér D., Björk O., Bröndum-Nielsen K., Söderhäll S. Deletion of α-, -β and o-IFN genes in malignant cells from children with acute lymphocytic leukemia. Cancer Res. 1990; 50: 7781 – 7785
39. Middleton P. G., Prince R. A., Williamson I. K., Taylor P. R. A., Reid M. M., Jackson G. H., Katz F., Chessells J. M., Proctor S. J. Alpha interferon gene deletions in adults, children and infants with acute lymphoblastic leukemia. Leukemia 1991; 5: 680 – 682
40. Fountain J., Karayiorgou M., Taruscio D., Graw S., Buckler A., Ward D., Dracopoli N., Housman D. Genetic and physical map of the interferon region on chromosome 9p. Genomics 1992; 14: 105 – 112
41. Olopade O., Bohlander S., Pomykala H., Maltepe E., Van Melle E., Le Beau M., Diaz M. Mapping of the shortest region of overlap of deletions of the short arm of chromosome 9 associated with human neoplasia. Genomics 1992; 14: 437 – 443
42. Serrano M., Hannon G., Beach D. A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993; 366: 704 – 707
43. Kamb A., Gruis N., Weaver-Feldhaus J., Liu Q., Harshman K., Tavtigian S., Stockert E., Day R., III, Johnson B., Skolnick M. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994; 263: 436 – 440
44. Nobori T., Miura K., Wu D., Lois A., Takabayashi K., Carson D. Deletions of the cyclin dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994; 368: 753 – 756
45. Hannon G., Beach D. p15INK4B is a potential effector of TGF-induced cell cycle arrest. Nature 1994; 371: 257 – 261
46. Duro D., Bernard O., Della Valle V., Berger R., Larsen C.-J. A new type of p16INK4/MTS1 gene transcript expressed in B-cell malignancies. Oncogene 1995; 11: 21 – 29
47. Stone S., Jian P., Dayananth P., Tavtigaian S., Katcher H., Parry D., Peters G., Kamb A. Complex structure and regulation of the P16 (MTS1) locus. Cancer Res. 1995; 55: 2988 – 2994
48. Mao L., Merlo A., Bedi G., Shapiro G., Edwards C., Rollins B., Sidransky D. A novel p16INK4A transcript. Cancer Res. 1995; 55: 2995 – 2997
49. Merlo A., Herman J., Mao L., Lee D., Gabrielson E., Burger P., Baylin S., Sidransky D. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nature Med 1995; 1: 686 – 692
50. Ewen M. E. The cell cycle and the retinoblastoma protein family. Cancer Metast. Rev. 1994; 13: 45 – 66
51. Hunter T., Pines J. Cyclins and cancer II: cyclin D and CDK inhibitors come of age. Cell 1994; 79: 573 – 582
52. Sherr C. J. The ins and outs of RB:coupling gene expression to the cell cycle clock. Trends Cell. Biol. 1994; 4: 15 – 18
53. Weinberg R. A. The retniblastoma protein and cell cycle control. Cell 1995; 81: 323 – 330
54. Sherr C. J., Roberts J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995; 9: 1149 – 1163
55. Graña X., Reddy E. P. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene 1995; 11: 211 – 219
56. Yang R., Gombart A. F., Serrano M., Koeffler H. P. Mutational effects on the p16INK4a tumor suppressor protein. Cancer Res. 1995; 55: 2503 – 2506
57. Wick S. T., Dubay M. M., Imanil I., Brizuela L. Biochemical and mutagenic analysis of the melanoma tumor suppressor gene product/p16. Oncogene 1995; 11: 2013 – 2019
58. Liu L., Lassam N. J., Slingerland J. M., Bailey D., Cole D., Jenkins R., Hogg D. Germline1 p16I NK4A mutation and protein dysfunction in a family with inherited melanoma. Oncogene 1995; 11: 405 – 412
59. Ranade K., Hussussian C. J., Sikorski R. S., Varmus H. E., Goldstein A. M., Tucker M. A., Serrano M., Hannon G. J., Beach D., Dracopoli N. C. Mutations associated with familial melanoma impair p 16INK4 function (letter). Nature Genet. 1995; 10: 114 – 6
60. Wölfel T., Hauer M., Schneider J., Serrano M., Wölfel C., Klehmann-Hieb E., De Plaen E., Hankeln T., Zum Büschenfelde K.-H. M., Beach D. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995; 269: 1281 – 1284
61. Okamoto A., Demetrick D., Spillare E., Hagiwara K., Hussain S., Bennett W., Forrester K., Gerwin B., Serrano M., Beach D., Harris C. Mutations and altered expression of p16INK4 in human cancer. Proc. Natl. Acad. Sci. USA 1994; 91: 11045 – 11049
62. Arap W., Nishikawa R., Furnari F. B., Cavenee W. K., Huang H. J. Replacement of the p16/CDKN2 gene suppresses human glioma cell growth. Cancer Res. 1995; 55: 1351 – 1354
63. Jin X., Nhuyen D., Zhang W.-W., Kyritsis A. P., Roth J. A. Cell cycle arrest and inhibition of tumor cell proliferation by the p16 INK4 gene mediated by an adenovirus vector. Cancer Res. 1995; 55: 3250 – 3253
64. Lukas J., Parry D., Aagaard L., Mann D. J., Bartkova J., Strauss M., Peters G., Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 1995; 375: 503 – 508
65. Koh J., Enders G. H., Dynlacht B. D., Harlow E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature 1995; 375: 506 – 510
66. Serrano M., Gómez-Lahoz E., De Pinho R., Beach D., Barsagi D. Inhibition of Ras-induced proliferation and cellular transformation by p16INK4. Science 1995; 267: 249 – 252
67. Stone S., Dayananth P., Jiang P., Weaver-Feldhaus J., Tavtigian S., Cannon-Albright L., Kamb A. Genomic structure, expression and mutational analysis of the P15 (MTS2) gene. Oncogene 1995; 11: 987 – 991
68. Kamb A. Cell-cycle regulators and cancer. Trends Genet. 1995; 11: 136 – 140
69. Tam S., Shay J., Pagano M. Differential expression and cell cycle regulation of the cycle-dependent kinase 4 inhibitor p16ink4. Cancer Res. 1994; 54: 5816 – 5820
70. Li Y., Nichols M., Shay J., Xiong Y. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 1994; 54: 6078 – 6082
71. Yeager T., Stadler W., Belair C., Puthenveettil J., Olopade O., Reznikoff C. Increased p16 levels correlate with pRb alterations in human urothelial cells. Cancer Res. 1995; 55: 493 – 497
72. Musgrove E. A., Lilischkis R., Cornish A. L., Lee S. I., Setlur V., Seshadri R., Sutherland R. L. Expression of the cyclin-dependent kinase inhibitors p16INK4 p15INK4B and p21WAFI/CIPI in human breast cancer. Int. J. Cancer 1995; 63: 584 – 591
73. Kelley M. J., Nakagawa K., Steinberg S. M., Mulshine J. L., Kamb A., Johnson B. E. Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines. J. Natl. Cancer Inst. 1995; 87: 756 – 761
74. Whitaker N. J., Bryan T. M., Bonnefin P., Chang A. C.-M., Musgrove E. A., Braithwaite A. W., Reddel R. R. Involvement of RB-1, p53, p16INK4 and telomerase in immortalisation of human cells. Oncogene 1995; 11: 971 – 976
75. Otterson G., Kratzke R., Coxon A. Y. W. K., Kaye F. Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wildtype RB. Oncogene 1994; 9: 3375 – 3378
76. Shapiro G. I., Edwards C. D., Kobzik L., Godleski J., Richards W., Sugarbaker D. J., Rollins B. J. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. Cancer Res. 1995; 55: 505 – 509
77. Parry D., Bates S., Mann D. J., Peters G. Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J. 1995; 14: 503 – 511
78. Reynisdóttir I., Polyak K., Iavarone A., Massagué J. Kip/Cip and Ink4 inhibitors cooperate to induce cell cycle arrest in response to TGF-β. Genes Dev. 1995; 9: 1831 – 1845
79. Li J.-M., Nichols M. A., Chandrasekharan S., Xiong Y., Wang X.-F. Transforming growth factor β activates the promoter of cyclin-dependent kinase inhibitor p15INK4B through an Spl consensus site. J. Biol. Chem. 1995; 270: 26750 – 26753
80. Kim S. J., Onwuta U. S., Lee Y. I., Li R., Botchan M. R., Robbins P. D. The retinoblastoma gene product regulates Spl-mediated transcription. Mol. Cell. Biol. 1992; 12: 2455 – 63
81. Udvadia A. J., Rogers K. T., Higgins P. D., Murata Y., Martin K. H., Humphrey P. A., Horowitz J. M. Sp-1 binds promoter elements regulated by the RB protein and Sp-1-mediated transcription is stimulated by RB coexpression. Proc. Natl. Acad. Sci. USA 1993; 90: 3265 – 3269
82. Udvadia A. J., Templeton D. J., Horowitz J. M. Functional interactions between the retinoblastoma (Rb) protein and Sp-family members: superactivation by Rb requires amino acids necessary for growth suppression. Proc. Natl. Acad. Sci. USA 1995; 92: 3953 – 3957
83. Lois A., Cooper L., Geng Y., Nobori T., Carson D. Expression of the p16 and p15 cyclin-dependent kinase inhibitors in lymphocyte activation and neuronal differentiation. Cancer Res. 1995; 55: 4010 – 4013
84. Gonzalez-Zulueta M., Bender C. M., Yang A. S., Td N., Beart R. W., Van Tornout J. M., Jones P. A. Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 1995; 55: 4531 – 4535
85. Herman J. G., Merlo A., Mao L., Lapidus R. G., Issa J.-P. J., Davidson N. E., Sidransky D., Baylin S. B. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995; 55: 4525 – 4530
86. Rasool O., Heyman M., Borgonova Brandter L., Liu Y., Grandér D., Söderhäll S., Einhorn S. p15ink4B and P16ink4 gene inactivation in acute lymphocytic leukemia. Blood 1995; 85: 3431 – 3436
87. Hebert J., Cayuela J., Berkeley J., Sigaux F. Candidate tumor suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T-but not from B- cell lineage acute lymphoblastic leukemias. Blood 1994; 84: 4038 – 4044
88. Okuda T., Shurtleff S., Valentine M., Raimondi S., Head D., Behm F., Curcio-Brint A., Liu Q., Pui C.-H., Sherr C., Beach D., Look A., Downing J. Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukemia. Blood 1995; 85: 2321 – 2330
89. Otsuki T., Clark H., Wellmann A., Jaffe E., Raffeld M. Involvement of CDKN2 (p16INK4A/MTS1) and p15INK4B/MTS2 in human leukemias and lymphomas. Cancer Res. 1995; 55: 1436 – 1440
90. Takeuchi S., Bartram C., Seriu T., Miller C., Tobler A., Janssen J., Reiter A., Ludwig W.-D., Zimmermann M., Schwaller J., Lee E., Miyoshi I., Koeffler H. Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood. Blood 1995; 86: 755 – 760
91. Rhyu M. S. Telomeres, telomerase and immortality. J. Natl. Cancer Inst. 1995; 87: 884 – 894
92. Rogan E. M., Bryan T. M., Hukku B., Maclean K., Chan A. C.-M., Moy E. L., Englezou A., Warneford S. G., Dalla-Pozza L., Reddel R. R. Alterations in p53 and p16INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts. Mol. Cell. Biol. 1995; 15: 4745 – 4753
93. Caldas C., Hahn S., Da Costa L., Redston M., Schutte M., Seymour A., Weinstein C., Hruban R., Yeo C., Kern S. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nature Genet. 1994; 8: 27 – 32
94. Goldstein A. M., Fraser M. C., Struewing J. P., Hussussian C. J., Ranade K., Zametkin D. P., Fontaine L. S., Organic S. M., Dracopoli N. C., Clark W. H., Jr., Tucker M. A. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16 INK4 mutations. N. Engl. J. Med. 1995; 333: 970 – 974
95. Whelan A. J., Bartsch D., Goodfellow P. J. A familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor suppressor gene. N. Engl. J. Med. 1995; 333: 975 – 977
96. Bartsch D., Shevlin D. W., Tung W. S., Kisker O., Wells S. A., Jr., Goodfellow P. J. Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas. Genes, Chromosomes Cancer 1995; 14: 189 – 195
97. Liu Q., Yan Y.-X., McClure M., Nakagawa H., Fujimura F., Rustgi A. MTS-1 (CDKN2) tumor suppressor gene deletions are a frequent event in esophagus squamous cancer and pancreatic adenocarcinoma cell lines. Oncogene 1995; 10: 619 – 622
98. Yoshida S., Todoroki T., Ichikawa Y., Hanai S., Suzuki H., Hori M., Fukao K., Miwa M., Uchida K. Mutations of p16 Ink4/CDKN2 and p15 Ink4B/MTS2 genes in biliary tract cancers. Cancer Res. 1995; 55: 2756 – 2760
99. Zhou X., Suzuki H., Shimada Y., Imamura M., Yin J., Jiang H.-Y., Tannin L., Abraham J., Meltzer S. Genomic DNA and messenger RNA expression alterations of the CDKN2B and CDKN2 genes in esophageal squamous carcinoma cell lines. Genes, Chromosomes Cancer 1995; 13: 285 – 290
100. Igaki H., Sasaki H., Tachimor Y., Kato H., Watanabe H., Kimura T., Harada Y., Sugimura T., Terada M. Mutation frequency of the p16/CDKN2 gene in primary cancers in the upper digestive tract. Cancer Res. 1995; 55: 3421 – 3423
101. Xiao S., Li D., Corson J. M., Vijg J., Fletcher J. A. Codeletions of p15 and p16 genes in primary non-small cell lung carcinoma. Cancer Res. 1995; 55: 2968 – 2971
102. Okamoto A., Hussain S. P., Hagiwara K., Spillare E. A., Rusin M. R., Demetrick D. J., Serrano M., Hannon G. J., Shiseki M., Zariwala M., Xiong Y., Beach D. H., Yokota J., Harris C. C. Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer. Cancer Res. 1995; 55: 1448 – 1451
103. De Vos S., Miller C. W., Takeuchi S., Gombart A. F., Cho S. K., Koeffler H. P. Alterations of CDKN2 (p16) in non-small cell lung cancer. Genes, Chromosomes Cancer 1995; 14: 164 – 170
104. Nakagawa K., Conrad N. K., Williams J. P., Johnson B. E., Kelley M. J. Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. Oncogene 1995; 11: 1843 – 1851
105. Liu Q., Neuhausen S., McDlure M., Frye C., Weaver-Feldhaus J., Gruis N. A., Eddington K., Allalunis-Turner M. J., Skolnick M. H., Fujimura F. K., Kamb A. CDKN2 (MTS1) tumor suppressor gene mutations in human tumor cell lines. Oncogene 1995; 10: 1061 – 1067
106. Washimi O., Nagatake M., Osada H., Ueda R., Koshikawa T., Seki T., Takahashi T., Takahashi T. In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non-small cell lung cancers. Cancer Res. 1995; 55: 514 – 517
107. Cairns P., Polascik T. J., Eby Y., Tokino K., Califano J., Merlo A., Mao L., Herath J., Jenkins R., Westra W., Rutter J. L., Buckler A., Gabrielson E., Tockman M., Cho K. R., Hedrick L., Bova G. S., Isaacs W., Koch W., Schwab D., Sidransky D. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nature Genet. 1995; 11: 210 – 212
108. Dreyling M. H., Bohlander S. K., Adeyanju M. O., Olopade O. I. Detection of CDKN2 deletions in tumor cell lines and primary glioma by interphase fluorescence in situ hybridization. Cancer Res. 1995; 55: 984 – 8
109. He J., Allen J., Collins V., Allalunis-Turner M., Godbout R., Day R., III, James C. CDK4 amplification is an alternative mechanism to p16 gene homozygous deletion in glioma cell lines. Cancer Res. 1994; 54: 5804 – 5807
110. Sonoda Y., Yoshimoto T., Sekiya T. Homozygous deletion of the MTS1/p16 and MTS2/p15 genes and amplification of the CDK4 gene in glioma. Oncogene 1995; 11: 2145 – 2149
111. Schmidt E. E., Ichimura K., Reifenberger G., Collins V. P. CDKN2 (p16/MTS1) gene deletions or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res. 1994; 54: 6321 – 6324
112. Walker D. G., Duan W., Popovic E. A., Kaye A. H., Tomlinson F. H., Lavin M. Homozygous deletions of the multiple tumor suppressor gene 1 in the progression of human astrocytomas. Cancer Res. 1995; 55: 20 – 23
113. Giani C., Finocchiaro G. Mutation rate of the CDKN2 gene in malignant gliomas. Cancer Res. 1994; 54: 6338 – 6339
114. Jen J., Harper J. W., Bigner S. H., Bigner D. D., Papadopoulos N., Markowitz S., Willson J. K. V., Kinzler K. W., Vogelstein B. Deletion of p16 and p15 genes in brain tumors. Cancer Res. 1994; 54: 6353 – 6358
115. Nishikawa R., Furnari F. B., Lin H., Arap W., Berger M. S., Cavenee W. K., Su H. H. Loss of P16INK4 expression is frequent in high grade gliomas. Cancer Res. 1995; 55: 1941 – 1945
116. Kamb A., Shattuck-Eidens D., Eeles R., Liu Q., Gruis N. A., Ding W., Hussey C., Tran T., Miki Y., Weaver-Feldhaus J., McClure M., Aitken J. F., Anderson D. E., Bergman W., Frants R., Goldar D. E., Green A., Maclennan R., Martin N. G., Meyer L. J., Youl P., Zone J. J., Skolnick M. H., Cannon-Albright L. A. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nature Genet. 1994; 8: 23 – 26
117. Hussussian C. J., Struewing J. P., Goldstein A. M., Higgins P. A., Ally D. S., Sheahan M. D., Clark W. H., Jr., Tucker M. A., Dracopoli N. C. Germline p16 mutations in familial melanoma. Nature Genet. 1994; 8: 15 – 21
118. Ohta M., Nagai H., Shimizu M., Rasio D., Berd D., Mastrangelo M., Sing A., Shields J., Croce C., Huebner K. Rarity of somatic and germline mutations of the cyclin-dependent kinase 4 inhibitor gene CDK41 in melanoma. Cancer Res. 1994; 54: 5269 – 5272
119. Gruis N. A., Weaver-Feldhaus J., Liu Q., Frye C., Eeles R., Orlow I., Lacombe L., Ponce-Castaneda V., Lianes P., Latres E., Skolnick M., Cordon-Cardo C., Kamb A. Genetic evidence in melanoma and bladder cancers that p16 and p53 function in separate pathways of tumor suppression. Am. J. Path. 1995; 146: 1199 – 1206
120. Luca M., Xie S., Gutman M., Huang S., Bar-Eli M. Abnormalities in the CDKN2(p16INK4/MTS-1) gene in human melanoma cells: relevance to tumor growth and metastasis. Oncogene 1995; 11: 1399 – 1402
121. Reed J. A., Loganzo F., Jr., Shea C. R., Walker G. J., Flores J. F., Glendening J. M., Bogdany J. K., Shiel M. J., Haluska F. G., Fountain J. W., Albino A. P. Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocyte lesions correlates with invasive stage of tumor progression. Cancer Res. 1995; 55: 2713 – 2718
122. Pollock P. M., Yu F., Qiu L., Parsons P. G., Hay Ward N. K. Evidence for u.v. induction of CDKN2 mutations in melanoma cell lines. Oncogene 1995; 11: 663 – 668
123. Gonzalez-Zulueta M., Shibata A., Ohneseit P., Spruck C., III, Busch C., Shamaa M., Elbaz M., Nichols P., Gonzalgo M., Malmström P.-U., Jones P. High frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder. J. Natl. Cancer Inst. 1995; 87: 1383 – 1393
124. Berns E., Klijn J., Smid M., Van Staveren I., Gruis N., Foekens J. Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer. Br. J. Cancer 1995; 72: 964 – 967
125. Brenner A. J., Aldaz C. M. Chromosome 9p allelic loss and p16/CDKN2 in breast cancer and evidence of p16 inactivation in immortal breast epithelial cells. Cancer Res. 1995; 55: 2892 – 2895
126. Xu L., Sgroi D., Sterner C. J., Beauchamp R. L., Pinney D. M., Keel S., Ueki K., Rutter J. L., Buckler A. J., Louis D. N., Gusella J. F., Ramesh V. Mutational analysis of CDKN2 (MTS1/p16ink4) in human breast carcinomas. Cancer Res. 1994; 54: 5262 – 5264
127. Campbell I. G., Beynon G., Davis M., Englefield P. LOH and mutation analysis of CDKN2 in primary human ovarian cancers. Int. J. Cancer 1995; 63: 222 – 225
128. Rodabaugh K., Biggs R., Qureshi J., Barrett A., Welch W., Bell D., Berkowitz R., Mok S. Detailed deletion mapping of chromosome 9p and p16 gene alterations in human borderline and invasive epithelial ovarian tumors. Oncogene 1995; 11: 1249 – 1254
129. Schultz D. C., Vanderveer L., Buetow K. H., Boente M. P., Ozols R. F., Hamilton T. C., Godwin A. K. Characterization of chromosome 9 in human ovarian neoplasia identifies frequent genetic imbalance on 9q and rare alterations involving 9p, including CDKN2. Cancer Res. 1995; 55: 2150 – 2157
130. Kelley M. J., Otterson G. A., Kaye F. J., Popescu N. C., Johnson B. E., Dipaolo J. A. CDKN2 in HPV-positive and HPV-negative cervical-carcinoma cell lines. Int. J. Cancer 1995; 63: 226 – 230
131. Sakata K., Tamura G., Maesawa C., Suzuki Y., Terashima M., Satoh K., Eda Y., Suzuki A., Sekiyama S., Satodate R. Loss of heterozygosity on the short arm of chromosome 9 without p16 gene mutation in gastric carcinomas. Jpn. J. Cancer Res. 1995; 86: 333 – 5
132. Quinn A. G., Sikkink S., Rees J. L. Delineation of two distinct deleted regions on chromosome 9 in human non-melanoma skin cancers. Genes, Chromosomes Cancer 1994; 11: 222 – 5
133. Beltinger C. P., White P. S., Sulman E. P., Maris J. M., Brodeur G. M. No CDKN2 mutations in neuroblastomas. Cancer Res. 1995; 55: 2053 – 2055
134. Cheng J. Q., Jhanwar S. C., Klein W. M., Bell D. W., Lee W. C., Altomare D. A., Nobori T., Olopade O. I., Buckler A. J., Testa J. R. p16 alterations and deletions mapping of 9p21-p22 in malignant mesotheliomas. Cancer Res. 1994; 54: 5547 – 5551
135. Sun Y., Hildesheim A., Lanier A. E. P., Cao Y., Yao K.-T., Raab-Traub N., Yang C.-S. No point mutation but decreased expression of the p16/MTS1 tumor suppressor gene in nasopharyngeal carcinomas. Oncogene 1995; 10: 785 – 788
136. Lo K. W., Huang D. P., Lau K. M. p16 gene alterations in nasopharyngeal carcinoma. Cancer Res. 1995; 55: 2039 – 2043
137. Lydiatt W. M., Murty V. V., Davidson B. J., Xu L., Dyomina K., Sacks P. G., Schantz S. P., Chaganti R. S. Homozygous deletions and loss of expression of the CDKN2 gene occur frequently in head and neck squamous cell carcinoma cell lines but infrequently in primary tumors. Genes, Chromosomes Cancer 1995; 13: 94 – 8
138. Zhang S.-Y., Klein-Szanto A., Sauter E., Shafarenko M., Mitsunaga S., Nobori M., Carson D., Ridge J., Goodrow T. Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck. Cancer Res. 1994; 54: 5050 – 5053
139. Orlow I., Lacom Be L., Hannon G. J., Serrano M., Pellicer I., Dalbagni G., Reuter V. E., Zhang Z.-F., Beach D., Cordon-Cardo C. Deletions of the p16 and p15 genes in human bladder tumors. J. Natl. Cancer Inst. 1995; 87: 1524 – 1529
140. Gruis N. A., Van Der Velden P. A., Sandkuijl L. A., Prins D. E., Weaver-Feldhaus J., Kamb A., Bergman W., Frants R. R. Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds. Nature Genet. 1995; 10: 351 – 353
141. Ogawa S., Hangaishi A., Miyawaki S., Hirosawa S., Miura Y., Takeyama K., Kamada N., Ohtake S., Uike N., Shimazaki C., Toyama K., Hirano M., Mizoguchi H., Kobayashi Y., Furusawa S., Saito M., Emi N., Yazaki Y., Ueda R., Hirai H. Loss of the cyclin-dependent kinase 4-inhibitor (p16;MTS1) gene is frequent in and highly specific to lymphoid tumors in primary human hematopoietic malignancies. Blood 1995; 86: 1548 – 1556
142. Quesnel B., Preudhomme C., Philippe N., Vanrumbeke M., Dervite I., Lai J., Bauters F., Wattel E., Fenaux P. P16 gene homozygous deletions in acute lymphoblastic leukemia. Blood 1995; 85: 657 – 663
143. Duro D., Flexor M.-A., Bernard O., DÁGay M.-F., Berger R., Larsen C.-J. Alterations of the putative tumor suppressor gene p16/MTS1 in human hematological malignancies. C. R. Acad. Sci. Paris 1994; 317: 913 – 919
144. Haidar M., Cao X.-B., Manshouri T., Chan L., Glassman A., Kantarjian H., Keating M., Beran M., Albitar M. p16INK4A and p15INK4B gene deletions in primary leukemias. Blood 1995; 86: 311 – 315
145. Sill H., Goldman J., Cross N. Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia. Blood 1995; 85: 2013 – 2016
146. Ohnishi H., Kawamura M., Ida K., Sheng X., Hanada R., Nobori T., Yamamori S., Hayashi Y. Homozygous deletions of p16/MTS1 gene are frequent but mutations are infrequent in childhood T-cell acute lymphoblastic leukemia. Blood 1995; 86: 1269 – 1275
147. Heyman M., Rasool O., Borgonovo Brandter L., Liu Y., Grandér D., Söderhäll S., Gustavsson G., Einhorn S. Prognostic importance of p15INK4B and p16INK4 gene inactivation in childhood acute lymphocytic leukemia. J. Clin. Oncol. 1996, In press
148. Uchida T., Watanabe T., Kinowhita T., Murate T., Saito H., Hotta T. Mutational analysis of the CDKN2 (MTS1/p16ink4A) gene in primary B-cell lymphomas. Blood 1995; 86: 2724 – 2731
149. Koduru P. R. K., Zariwala M., Soni M., Gong J. Z., Xiong Y., Broome J. D. Deletion of cyclin-dependent kinase 4 inhibitor genes P15 and P16 in non-Hodgkin's lymphoma. Blood 1995; 86: 2900 – 2905
150. Gombart A., Morosetti R., Miller C., Said J., Koeffler H. Deletions of the cyclin-dependent kinase inhibitor genes p16INK4A and p15INK4B in non-hodgkin's lymphomas. Blood 1995; 86: 1534 – 1539
151. Cairns P., Mao L., Merlo A., Lee D. J., Schwab D., Eby Y., Tokino K., Van Der Riet P., Blaugrund J. E., Sidransky D. Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science 1994; 265: 415 – 416
152. Spruck C., III, Gonzales-Zulueta M., Shibata A., Simoneau A., Lin M.-F., Gonzales F., Tsal Y., Jones P. p16 gene in cultured tumours. Nature 1994; 370: 183 – 184
153. Borgonovo Brandter L., Heyman M., Rasool O., Liu Y., Grandér D., Einhorn S. p16INK4B/p15INK4B gene inactivation is a frequent event in malignant T-cell lines. Eur. J. Haematol. 1996, In press
154. Heyman M., Rasool O., Borgonovo Brandter L., Liu Y., Grander D., Einhorn S. “Exclusive” p15INK4B gene deletions in acute lymphocytic leukemia include the E1β exon of the p16INK4 gene. (1996). Blood 1996, In press
155. Riehm H., Gadner H., Henze G., Komhuber B., Lampert F., Niethammer D., Reiter A., Schellong G. Results and significance of six randomized trials in four consecutive ALL-BFM studies. Haematol. Blood. Transf. 1990; 33: 439 – 456
156. Pui C.-H., Crist W. Treatment of childhood leukemias. Curr. Opin. Oncol. 1995; 7: 36 – 44
157. Rivera G., Pinkel D., Simone J., Hancock M., Crist W. Treatment of acute lymphoblastic leukemia 30 years experience at St. Jude Children's research hospital. N. Engl. J. Med. 1993; 329: 1289 – 1295
158. Yu A. L., Diccianni M. B., Batova A., Vu T., Pullen J., Amylon M., Pollock B., Yu J. High frequency alterations of the p16 and p15, but not p18, CDK inhibitors in T cell acute lymphoblastic leukemia, (abstract). Blood 1995; 86: 268a
159. Stock W., Sher D. A., Dodge R. K., Westbrook C. A., Larson R. A., Frankel S. R., Soble R. E., Davey F. R., Schneider D., Diaz M. O., Bloomfield C. D. High incidence of p16 deletion in adult acute lymphoblastic leukemia (ALL): Correlation with clinical features and response to treatment: CALGB 8762. Blood 1995; 86: 268a, (abstract)
160. Dreyling M. H., Bohlander S. K., Vardiman J. R., Olopade O. I. CDKN2 deletion is a frequent event in the histologic transformation to diffuse large cell lymphoma, (abstract). Blood 1995; 86: 329a
161. Quelle D. E., Zindy F., Ashmun R. A., Sherr C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995; 83: 993 – 1000