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Prognostic implications of epigenetic silencing of p15INK4B in acute promyelocytic leukemia

Leukemia volume 17, pages 839–840 (2003)Cite this article

In this issue of Leukemia, Teofili et al1 report the prognostic value of aberrant DNA methylation of the p15 gene in acute promyelocytic leukemia (APL). Cytosine guanine (CpG) pairs are under-represented in the human genome except in areas known as CpG islands where their frequency is near that of predicted. CpG islands can be found in the proximity of gene promoter regions and in noncoding intergenic areas characterized by highly repetitive DNA sequences.2 CpG pairs are the target of a biochemical modification, known as DNA methylation, that consists in the addition of a methyl group to the fifth position in the cytosine of the CpG pair.3 In a non-neoplastic cell, promoter-associated CpG islands tend to be not methylated, except in cases of imprinted genes or those located on the X chromosome in females where methylation is presumed to control gene dosage.4,5 In contrast, the CpG-rich regions found in intergenic areas tend to be methylated in non-neoplastic cells, a phenomenon that has been proposed to defend the cell from the activation of foreign DNA sequences and to preserve genome integrity.3,6 A switch in this methylation pattern with malignant transformation is observed by which promoter-associated CpG islands may become methylated, and intergenic CpG islands may lose methylation.7

The regulatory mechanisms that control CpG methylation in normal and neoplastic cells are not fully understood. Several enzymes, known as DNA methyltransferases (DNMTs), have been isolated.8,9 Lack of DNMT3b has been found in patients with the ICF syndrome,9,10 a rare autosomal recessive disorder, but so far a clear association between aberrant DNMT function and oncogenesis has not been found. The concordant methylation of multiple promoter-associated CpG islands has been observed in different malignancies including solid tumors and leukemias.11,12,13 The fact that methylation of these CpG islands is closely associated suggests that this phenomenon is not random but the result of a defect in the control of methylation in neoplastic cells.

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References

  1. Teofili L, Martini M, Luongo M, Diverio D, Capelli G, Breccia M et al. Hypermethylation of CpG islands in the promoter region of p15INK4b in acute promyelocytic leukemia repress p15INK4b expression and correlates with poor prognosis. Leukemia 2003; 17: 919–924.

    Article  CAS  Google Scholar 

  2. Bird A . The essentials of DNA methylation. Cell 1992; 70: 5–8.

    Article  CAS  Google Scholar 

  3. Robertson KD, Wolffe AP . DNA methylation in health and disease. Nat Rev Genet 2000; 1: 11–19.

    Article  CAS  Google Scholar 

  4. Li E, Beard C, Jaenisch R . Role for DNA methylation in genomic imprinting. Nature 1993; 366: 362–365.

    Article  CAS  Google Scholar 

  5. Goto T, Monk M . Regulation of X-chromosome inactivation in development in mice and humans. Microbiol Mol Biol Rev 1998; 62: 362–378.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bestor TH, Tycko B . Creation of genomic methylation patterns. Nat Genet 1996; 12: 363–367.

    Article  CAS  Google Scholar 

  7. Jones PA, Baylin SB . The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415–428.

    Article  CAS  Google Scholar 

  8. Bird A . DNA methylation de novo. Science 1999; 286: 2287–2288.

    Article  CAS  Google Scholar 

  9. Okano M, Bell DW, Haber DA, Li E . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999; 99: 247–257.

    Article  CAS  Google Scholar 

  10. Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 1999; 402: 187–191.

    Article  CAS  Google Scholar 

  11. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP . CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 1999; 96: 8681–8686.

    Article  CAS  Google Scholar 

  12. Toyota M, Kopecky KJ, Toyota MO, Jair KW, Willman CL, Issa JP . Methylation profiling in acute myeloid leukemia. Blood 2001; 97: 2823–2829.

    Article  CAS  Google Scholar 

  13. Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM, et al. DNA methylation of multiple promoter-associated CpG Islands in adult acute lymphocytic leukemia. Clin Cancer Res 2002; 8: 2217–2224.

    CAS  PubMed  Google Scholar 

  14. Wolffe AP, Matzke MA . Epigenetics: regulation through repression. Science 1999; 286: 481–486.

    Article  CAS  Google Scholar 

  15. Eden S, Cedar H . Role of DNA methylation in the regulation of transcription. Curr Opin Genet Dev 1994; 4: 255–259.

    Article  CAS  Google Scholar 

  16. Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M et al. Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000; 18: 956–962.

    Article  CAS  Google Scholar 

  17. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002; 20: 2429–2440.

    Article  CAS  Google Scholar 

  18. Melki JR, Vincent PC, Clark SJ . Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res 1999; 59: 3730–3740.

    CAS  Google Scholar 

  19. Issa JP, Kantarjian H, Mohan A, O'Brien S, Cortes J, Pierce S et al. Methylation of the ABL1 promoter in chronic myelogenous leukemia: lack of prognostic significance. Blood 1999; 93: 2075–2080.

    CAS  PubMed  Google Scholar 

  20. Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB . Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res 1997; 57: 837–841.

    CAS  Google Scholar 

  21. Ben-Yehuda D, Krichevsky S, Rachmilewitz EA, Avraham A, Palumbo GA, Frassoni F et al. Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia. Blood 1997; 90: 4918–4923.

    CAS  PubMed  Google Scholar 

  22. Shteper PJ, Siegfried Z, Asimakopoulos FA, Palumbo GA, Rachmilewitz EA, Ben-Neriah Y et al. ABL1 methylation in Ph-positive ALL is exclusively associated with the P210 form of BCR-ABL. Leukemia 2001; 15: 575–582.

    Article  CAS  Google Scholar 

  23. Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 2002; 295: 1079–1082.

    Article  CAS  Google Scholar 

  24. Chim CS, Liang R, Tam CY, Kwong YL . Methylation of p15 and p16 genes in acute promyelocytic leukemia: potential diagnostic and prognostic significance. J Clin Oncol 2001; 19: 2033–2040.

    Article  CAS  Google Scholar 

  25. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996; 93: 9821–9826.

    Article  CAS  Google Scholar 

  26. Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA 1992; 89: 1827–1831.

    Article  CAS  Google Scholar 

  27. Garcia-Manero G, Bueso-Ramos C, Daniel J, Williamson J, Kantarjian HM, Issa JP . DNA methylation patterns at relapse in adult acute lymphocytic leukemia. Clin Cancer Res 2002; 8: 1897–1903.

    CAS  PubMed  Google Scholar 

  28. Jenuwein T, Allis CD . Translating the histone code. Science 2001; 293: 1074–1080.

    Article  CAS  Google Scholar 

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  1. Department of Leukemia, University of Texas MD Anderson Cancer Center Houston, TX, USA

    Guillermo Garcia-Manero

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Garcia-Manero, G. Prognostic implications of epigenetic silencing of p15INK4B in acute promyelocytic leukemia. Leukemia 17, 839–840 (2003). https://doi.org/10.1038/sj.leu.2402908

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