DOI QR코드

DOI QR Code

Low Level of TERC Gene Amplification between Chronic Myeloid Leukaemia Patients Resistant and Respond to Imatinib Mesylate Treatment

  • Mohamad Ashari, Zaidatul Shakila (Human Genome Center, School of Medical Sciences, Health Campus, Universiti Sains Malaysia) ;
  • Sulong, Sarina (Human Genome Center, School of Medical Sciences, Health Campus, Universiti Sains Malaysia) ;
  • Hassan, Rosline (Department of Haematology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia) ;
  • Husin, Azlan (Haemato-Oncology Unit, Department of Internal Medicine, School of Medical Sciences, Health Campus, Universiti Sains Malaysia) ;
  • Sim, Goh Ai (Hospital Pulau Pinang) ;
  • Wahid, S. Fadilah Abdul (Department of Medicine & Cell Therapy Center, Universiti Kebangsaan Malaysia Medical Center)
  • Published : 2014.02.28

Abstract

The amplification of telomerase component (TERC) gene could play an important role in generation and treatment of haematological malignancies. This present study was aimed to investigate copy number amplification status of TERC gene in chronic myeloid leukaemia (CML) patients who were being treated with imatinib mesylate (IM). Genomic DNA was extracted from peripheral blood of CML-IM Resistant (n=63), CML-IM Respond (n=63) and healthy individuals (n=30). TERC gene copy number predicted (CNP) and copy number calculated (CNC) were determined based on $Taqman^{(R)}$ Copy Number Assay. Fluorescence in situ hybridization (FISH) analysis was performed to confirm the normal signal pattern in C4 (calibrator) for TERC gene. Nine of CML patients showed TERC gene amplification (CNP=3), others had 2 CNP. A total of 17 CML patients expressed CNC>2.31 and the rest had 2.31>CNC>1.5. TERC gene CNP value in healthy individuals was 2 and their CNC value showed in range 1.59-2.31. The average CNC TERC gene copy number was 2.07, 1.99 and 1.94 in CML-IM Resistant patients, CML-IM Respond and healthy groups, respectively. No significant difference of TERC gene amplification observed between CML-IM Resistant and CML-IM Respond patients. Low levels of TERC gene amplification might not have a huge impact in haematological disorders especially in terms of resistance towards IM treatment.

Keywords

Telomerase RNA component;gene amplification;CML;imatinib mesylate resistance

References

  1. Reichard KK, Hall BK, Corn A, et al (2006). Automated analysis of fluorescence in situ hybridization on fixed, paraffinembedded whole tissue sections in B-cell lymphoma. Modern Pathology, 19, 1027-33. https://doi.org/10.1038/modpathol.3800630
  2. Ozer O, Balci TB, Yilmaz Z, et al (2011). Fluorescence in situ hybridization analysis of the hTERC region in acute myeloid leukemia patients. Turkish J Hematology, 28, 103-6. https://doi.org/10.5152/tjh.2011.25
  3. Podlevsky JD, Bley CJ, Omana RV, et al (2008). The telomerase database. Nucleic Acids Res, 36, 339-43.
  4. Quintas-Cardama A, Kantarjian HM, Cortes JE (2009). Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia. Cancer Control, 16, 122-31. https://doi.org/10.1177/107327480901600204
  5. Serakinci N, Koch JE (2002). Telomerase activity in human leukemic cells with or without monosomy 7 or 7q. BMC Medical Genetics, 3, 11.
  6. Shay JW, Bacchetti S (1997). A survey of telomerase activity in human cancer. Eur J Cancer, 33, 787-91. https://doi.org/10.1016/S0959-8049(97)00062-2
  7. Soder AI, Hoare SF, Muir S, et al (1997). Amplification, increased dosage and in situ expression of the telomerase RNA gene in human cancer. Oncogene, 14, 1013- 21. https://doi.org/10.1038/sj.onc.1201066
  8. Wright WE, Piatyszek MA, Rainey WE, et al (1996). Telomerase activity in human germline and embryonic tissues and cells. Dev Genet, 18, 173-9. https://doi.org/10.1002/(SICI)1520-6408(1996)18:2<173::AID-DVG10>3.0.CO;2-3
  9. Yamada O, Kawauchi K, Akiyama M, et al (2008). Leukemic cells with increased telomerase activity exhibit resistance to imatinib. Leukemia Lymphoma, 49, 1168-77. https://doi.org/10.1080/10428190802043861
  10. Kokalj-Voka AN, Kodri AT, Erjavec-Kerget A, et al (2009). Screening of TERC gene amplification as an additional genetic diagnostic test in detection of cervical preneoplastic lesions. Cancer Genetics Cytogenetics, 195, 19-22. https://doi.org/10.1016/j.cancergencyto.2009.01.005
  11. Gurkan E, Tanriverdi K, Baslamisli F (2005). Telomerase activity in myelodysplastic syndromes. Leukemia Res, 29, 1131-9. https://doi.org/10.1016/j.leukres.2005.03.006
  12. Heselmeyer-Haddad K, Sommerfeld K, White NM, et al (2005). Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer. Am J Pathol, 166, 1229-38. https://doi.org/10.1016/S0002-9440(10)62341-3
  13. Kim NW, Piatyszek MA, Prowse KR, et al (1994). Specific association of human telomerase activity with immortal cells and cancer. Science, 266, 2011-15. https://doi.org/10.1126/science.7605428
  14. Kyo S, Takakura M, Fujiwara T, Inoue M (2008). Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. Cancer Sci, 99, 1528-38. https://doi.org/10.1111/j.1349-7006.2008.00878.x
  15. Liu Y, Dong XL, Tian C, et al (2012). Human telomerase RNA component (hTERC) gene amplification detected by FISH in precancerous lesions and carcinoma of the larynx. Diagnostic Pathol, 7, 34. https://doi.org/10.1186/1746-1596-7-34
  16. Masutomi K, Yu EY, Khurts S, et al (2003). Telomerase maintains telomere structure in normal human cells. Cell, 114, 241-53. https://doi.org/10.1016/S0092-8674(03)00550-6
  17. Mitelman F, Johansson B, Mertens F (2004). Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nature Genetics, 36, 331-4. https://doi.org/10.1038/ng1335
  18. Nowak T, Januszkiewicz D, Zawada M, et al (2006). Amplification of hTERT and hTERC genes in leukemic cells with high expression and activity of telomerase. Oncol Rep, 16, 301-5.
  19. Ohyashiki JH, Sashida G, Tauchi T, et al (2002). Telomeres and telomerase in hematologic neoplasia. Oncogene, 21, 680-7. https://doi.org/10.1038/sj.onc.1205075
  20. Cong YS, Wright WE, Shay JW (2002). Human telomerase and its regulation. Microbiol Mol Biol Rev, 66, 407-25. https://doi.org/10.1128/MMBR.66.3.407-425.2002
  21. Cao Y, Bryan TM, Reddel RR (2008). Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells. Cancer Sci, 99, 1092-99. https://doi.org/10.1111/j.1349-7006.2008.00815.x
  22. Chen M, Xing L-N (2012) siRNA-mediated inhibition of hTERC enhances radiosensitivity of cervical cancer. Asian Pac J Cancer Prev, 13, 5975-9. https://doi.org/10.7314/APJCP.2012.13.12.5975
  23. Chen Q, Wang X, Ru Y, et al (2011) Amplification of the telomerase RNA component gene in the process of human esophageal carcinogenesis. Tohoku J Exp Med, 224, 99-104. https://doi.org/10.1620/tjem.224.99
  24. Cortes J, Hochhaus A, Hughes T, et al (2011). Front-line and salvage therapies with tyrosine kinase inhibitors and other treatments in chronic myeloid leukemia. J Clin Oncol, 29, 524-31. https://doi.org/10.1200/JCO.2010.31.3619
  25. Gabert J, Beillard E, Van der Velden V, et al (2003). Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia-a Europe against cancer program. Leukemia, 17, 2318-57. https://doi.org/10.1038/sj.leu.2403135
  26. Goldman JM (2008). Chronic myeloid leukaemia. Medicine, 37, 195-7.
  27. Gozzetti A, Le Beau MM (2000). Fluorescence in situ hybridization: uses and limitations. Semin Hematol, 37, 320-33. https://doi.org/10.1016/S0037-1963(00)90013-1
  28. Graf SW, Lester S, Nossent JC, et al (2012). Low copy number of the FCGR3B gene and rheumatoid arthritis: a case-control study and meta-analysis. Arthritis Res Ther, 14, 28.
  29. Gugliotta G, Castagnetti F, Palandri F, et al (2011). Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CMLWorking Party. Blood, 117, 5591-99. https://doi.org/10.1182/blood-2010-12-324228
  30. Albertson DG, Collins C, McCormick F, et al (2003). Chromosome aberrations in solid tumours. Nature Genetics, 34, 369-76. https://doi.org/10.1038/ng1215
  31. Andersson S, Wallin KL, Hellstro AC, et al (2006). Frequent gain of human telomerase gene TERC at 3q26 in Cervical Adenocarcinomas. Br J Cancer, 95, 331-8. https://doi.org/10.1038/sj.bjc.6603253
  32. Bakalova R, Ohba H, Zhelev Z, et al (2003). Cross-talk between Bcr-Abl tyrosine kinase, protein kinase C and telomerase-a potential reason for resistance to Glivec in chronic myelogenous leukaemia. Biochem Pharmacol, 66, 1879-84. https://doi.org/10.1016/j.bcp.2003.06.001
  33. Bignold LP (2006) Cancer: Cell Structures, Carcinogens and Genomic Instability, Springer, 1-19.
  34. Breccia M, Efficace F, Alimena G (2010). Imatinib treatment in chronic myelogenous leukemia: what have we learned so far? Cancer Lett, 300, 115-21.

Cited by

  1. Chronic Myeloid Leukemia - Prognostic Value of Mutations vol.16, pp.17, 2015, https://doi.org/10.7314/APJCP.2015.16.17.7415
  2. Regulatory network analysis of microRNAs and genes in imatinib-resistant chronic myeloid leukemia vol.17, pp.2-3, 2017, https://doi.org/10.1007/s10142-016-0520-1