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Restriction landmark genome scanning for aberrant methylation in primary refractory and relapsed acute myeloid leukemia; involvement of the WIT-1 gene

Abstract

There is substantial evidence to suggest that aberrant DNA methylation in the regulatory regions of expressed genes may play a role in hematologic malignancy. In the current report, the Restriction Landmark Genomic Scanning (RLGS) method was used to detect aberrant DNA methylation (M) in acute myeloid leukemia (AML). RLGS-M profiles were initially performed using DNA from diagnostic, remission, and relapse samples from a patient with AML. Rp18, one of the eight spots found that was absent in the relapse sample, was cloned. Sequence analysis showed that the spot represented a portion of the WIT-1 gene on human chromosome 11p13. Rp18 was missing in the relapse sample due to a distinct DNA methylation pattern of the WIT-1 gene. Twenty-seven AML patients that entered CR after therapy (i.e., chemosensitive) were studied and only 10 (37%) of the diagnostic bone marrow (BM) samples showed methylation of WIT-1. However, seven of eight (87.5%) diagnostic BM samples from primary refractory AML (chemosensitive) showed methylation of WIT-1. The incidence of WIT-1 methylation in primary refractory AML was significantly higher than that noted in chemosensitive AML (P=0.018). Together, these results indicate that RLGS-M can be used to find novel epigenetic alterations in human cancer that are undetectable by standard methods. In addition, these results underline the potential importance of WIT-1 methylation in chemoresistant AML.

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References

  • Akama TO, Okazaki Y, Ito M, Okuizumi H, Konno H, Muramatsu M, Plass C, Held WA and Hayashizaki Y. . 1997 Cancer Res. 57: 3294–3299.

  • Baylin SB, Hoppener JW, de Bustros A, Steenbergh PH, Lips CJ and Nelkin BD. . 1986 Cancer Res. 46: 2917–2922.

  • Baylin SB, Herman JG, Graff JR, Vertino PM and Issa JP. . 1998 Adv. Cancer Res. 72: 141–196.

  • Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR and Sultan C. . 1985 Ann. Intern. Med. 103: 620–625.

  • Bergmann L, Karakas T, Miething C, Maurer U, Weidmann E and Hoelzer D. . 1997 Blood 90: 561a.

  • Caligiuri MA, Strout MP and Gilliland DG. . 1997 Semin. Oncol. 24: 32–44.

  • Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ, Sawitsky A, Stass S, Weinstein H and Woods WG. . 1990 J. Clin. Oncol. 8: 813–819.

  • Costello JF, Plass C, Arap W, Chapman VM, Held WA, Berger MS, Su Huang HH and Cavenee WK. . 1997 Cancer Res. 57: 1250–1254.

  • deBustros A, Nelkin BD, Silverman A, Ehrlich G, Poiesz B and Baylin S. . 1988 Proc. Natl. Acad. USA 85: 5693–5697.

  • Gessler M and Bruns GA. . 1993 Genomics 17: 499–501.

  • Gonzalgo ML, Liang G, Spruck III, CH, Zingg JM, Rideout III WM and Jones PA. . 1997 Cancer Res. 57: 594–599.

  • Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ and Baylin SB. . 1997 Cancer Res. 57: 837–841.

  • Hiltunen MO, Koistinaho J, Alhonen L, Myohanen S, Marin S, Kosma VM, Paakkonen M and Janne J. . 1997 Br. J. Cancer 76: 1124–1130.

  • Huang A, Campbell CE, Bonetta L, McAndrews-Hill MS, Chilton-MacNeill S, Coppes MJ, Law DJ, Feinberg AP, Yeger H and Williams BR. . 1990 Science 250: 991–994.

  • Inoue K, Ogawa H, Sonoda Y, Kimura T, Sakabe H, Oka Y, Miyake S, Tamaki H, Oji Y, Yamagami T, Tatekawa T, Soma T, Kishimoto T and Sugiyama H. . 1997 Blood 89: 1405–1412.

  • Issa JP, Zehnbauer BA, Civin CI, Collector MI, Sharkis SJ, Davidson NE, Kaufmann SH and Baylin SB. . 1996 Cancer Res. 56: 973–977.

  • Issa JP, Baylin SB and Herman JG. . 1997a Leukemia 11 Suppl 1: S7–S11.

  • Issa JP, Zehnbauer BA, Kaufmann SH, Biel MA and Baylin SB. . 1997b Cancer Res. 57: 1678–1681.

  • Jinno Y, Yun K, Nishiwaki K, Kubota T, Ogawa O, Reeve AE and Niikawa N. . 1994 Nat. Genet. 6: 305–309.

  • Neumann B, Kubicka P and Barlow DP. . 1995 Nat. Genet. 9: 12–13.

  • Okazaki Y, Okuizumi H, Sasaki N, Ohsumi T, Kuromitsu J, Horota N, Muramatsu M and Hayashizaki Y. . 1995 Electrophoresis 16: 197–202.

  • Palumbo A, Minowada J, Erikson J, Croce CM and Rovera G. . 1984 Blood 64: 1059–1063.

  • Plass C, Shibata H, Kalcheva I, Mullins L, Kotelevtseva N, Mullins J, Kato R, Sasaki H, Hirotsune S, Okazaki Y, Held WA, Hayashizaki Y and Chapman VM. . 1996 Nat. Genet. 14: 106–109.

  • Plass C, Weichenhan D, Catanese J, Costello JF, Yu F, Yu L, Smiraglia D, Cavenee WK, Calgiuri MA, de Jong P and Held WA. . 1997 DNA Res. 4: 253–255.

  • Sambrook J, Fritsch E and Maniatis T. . 1989 Molecular cloning: A laboratory manual 2nd edn. Cold Spring Harbor Lab Press, Plainview, NY.

    Google Scholar 

  • Taoka T, Tasaka T, Tanaka T, Irino S and Norman AW. . 1992 Blood 80: 46–52.

  • Tycko B. . 1994 Am. J. Pathol. 144: 431–443.

  • Ushijima T, Morimura K, Hosoya Y, Okonogi H, Tatematsu M, Sugimura T and Nagao M. . 1997 Proc. Natl. Acad. Sci. USA 94: 2284–2289.

  • Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M, Kudoh T, Akiyama T, Murakami A and Maekawa T. . 1996 Blood 87: 2878–2884,

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Acknowledgements

This work was supported in part by grant P30 CA16058, National Cancer Institute, Bethesda, MD, 2RO1CA68612, and the Coleman Leukemia Research Foundation. CP was supported by grants 1RO1GM58269, and IR21CA80912.

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Plass, C., Yu, F., Yu, L. et al. Restriction landmark genome scanning for aberrant methylation in primary refractory and relapsed acute myeloid leukemia; involvement of the WIT-1 gene. Oncogene 18, 3159–3165 (1999). https://doi.org/10.1038/sj.onc.1202651

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