Advertisement

Low prevalence of the BCRABL1 fusion gene in a normal population in southern Sarawak

  • Jew Win KuanEmail author
  • Anselm Ting Su
  • Siow Phing Tay
  • Isabel Lim Fong
  • Sho Kubota
  • Lela Su’ut
  • Motomi Osato
  • Goro SashidaEmail author
Original Article

Abstract

The BCRABL1 fusion gene is the driver mutation of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Its expression level in CML patients is monitored by a real-time quantitative polymerase chain reaction defined by the International Scale (qPCRIS). BCRABL1 has also been found in asymptomatic normal individuals using a non-qPCRIS method. In the present study, we examined the prevalence of BCRABL1 in a normal population in southern Sarawak by performing qPCRIS for BCRABL1 with ABL1 as an internal control on total white blood cells, using an unbiased sampling method. While 146 of 190 (76.8%) or 102 of 190 (53.7%) samples showed sufficient amplification of the ABL1 gene at > 20,000 or > 100,000 copy numbers, respectively, in qPCRIS, one of the 190 samples showed amplification of BCRABL1 with positive qPCRIS of 0.0023% and 0.0032% in two independent experiments, the sequence of which was the BCRABL1 e13a2 transcript. Thus, we herein demonstrated that the BCRABL1 fusion gene is expected to be present in approximately 0.5–1% of normal individuals in southern Sarawak.

Keywords

Chronic myeloid leukemia Asymptomatic people Clonal hematopoiesis 

Notes

Acknowledgments

We would like to thank Dr. Sai Peng Sim for allowing the usage of the Medical Molecular Genetic Laboratory, UNIMAS and supporting the study, Dr. Yuwana Podin for allowing the storage of RNA samples at the Institute of Health and Community Medicine, UNIMAS, staff from IRCMS, Kumamoto University and FMHS, UNIMAS for assisting this study. We also would like to thank Dr. Jameela Sathar and Phan Chin Lee from Ampang Hospital, Malaysia for assessing the RT-PCR data by NRL. This study was supported by the Japan Society for the Promotion of Science (JSPS) RONPAKU (Dissertation PhD) Program FY2017, UNIMAS Special Grant Scheme no: F05/SpGS/1401/16/2, Fundamental Research Grant Scheme no: FRGS/SKK01(01)/1290/2015(7) and FMHS, UNIMAS under Research no: FPSK/FPI/(F09)/2017/(14).

Author contributions

JWK conceived, designed, planned, and conducted the entire research, collected, analyzed, and interpreted the data, and wrote the manuscript. ATS designed, planned, and conducted samplings and provided statistical consultation. SPT conducted two of the samplings and performed FBC and smears of PB films. IFL supervised/supported blood lysis and RNA extraction. SK provided technical consultation on qPCR and performed validation of the positive subject. LS supervised and supported the research. MO co-supervised the research and provided technical support. GS supervised the research, provided technical support and consultation, and wrote the manuscript. All authors participated in revising the manuscript and its final approval.

Compliance with ethical standards

Conflict of interest

All authors declared no conflicts of interest.

Supplementary material

12185_2019_2768_MOESM1_ESM.docx (37 kb)
Supplementary material 1 (DOCX 37 kb)
12185_2019_2768_MOESM2_ESM.docx (24 kb)
Supplementary material 2 (DOCX 23 kb)
12185_2019_2768_MOESM3_ESM.docx (14 kb)
Supplementary material 3 (DOCX 13 kb)
12185_2019_2768_MOESM4_ESM.docx (15 kb)
Supplementary material 4 (DOCX 15 kb)

References

  1. 1.
    Chandra HS, Heisterkamp NC, Hungerford A, Morrissette JJ, Nowell PC, Rowley JD, et al. Philadelphia chromosome symposium: Commemoration of the 50th anniversary of the discovery of the Ph chromosome. Cancer Genet. 2011;204(4):171–9.CrossRefGoogle Scholar
  2. 2.
    Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960;25:85–109.PubMedGoogle Scholar
  3. 3.
    Rowley JD. Citation classic. Curr Content/Life Sci. 1988;1988:16.Google Scholar
  4. 4.
    Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells. Nat Med. 1996;2(5):561–6.CrossRefGoogle Scholar
  5. 5.
    Kantarjian H, O’Brien S, Jabbour E, Garcia-Manero G, Quintas-Cardama A, Shan J, et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood. 2012;119(9):1981–7.CrossRefGoogle Scholar
  6. 6.
    Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809–20.CrossRefGoogle Scholar
  7. 7.
    Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR–ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1):28–37.CrossRefGoogle Scholar
  8. 8.
    Vardiman JW, Melo JV, Baccarani M, Thiele J. Chronic myeloid leukemia, BCRABL1-positive. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri AS, et al., editors. WHO classification of tumors of hematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press; 2017. p. 32–7.Google Scholar
  9. 9.
    Kuan JW, Su AT, Leong CF, Osato M, Sashida G. Systematic review of pre-clinical chronic myeloid leukaemia. Int J Hematol. 2018;108(5):465–84.CrossRefGoogle Scholar
  10. 10.
    Kuan JW, Su AT, Leong CF, Osato M, Sashida G. Systematic review of normal subjects harbouring BCRABL1 fusion gene. Acta Haematol. 2019;9:1–16.CrossRefGoogle Scholar
  11. 11.
    Cross NC, White HE, Colomer D, Ehrencrona H, Foroni L, Gottardi E, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015;29(5):999–1003.CrossRefGoogle Scholar
  12. 12.
    Department of Statistics. Population distribution and basic demographic characteristics 2010. Population and housing census of Malaysia. Kuala Lumpur: Department of Statistics, Malaysia; 2011.Google Scholar
  13. 13.
    Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54.CrossRefGoogle Scholar
  14. 14.
    Kuan JW, Melaine Michael S. The epidemiology of chronic myeloid leukaemia in southern Sarawak, Borneo Island. Med J Malaysia. 2018;73(2):78–85.PubMedGoogle Scholar
  15. 15.
    Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16.CrossRefGoogle Scholar
  16. 16.
    Bose S, Deininger M, Gora-Tybor J, Goldman JM, Melo JV. The presence of typical and atypical BCR–ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood. 1998;92(9):3362–7.CrossRefGoogle Scholar
  17. 17.
    Ismail SI, Naffa RG, Yousef AMF, Ghanim MT. Incidence of bcr–abl fusion transcripts in healthy individuals. Mol Med Rep. 2014;9(4):1271–6.CrossRefGoogle Scholar
  18. 18.
    Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–65.CrossRefGoogle Scholar
  19. 19.
    Steensma DP. Clinical consequences of clonal hematopoiesis of indeterminate potential. Hematol Am Soc Hematol Educ Program. 2018;2018(1):264–9.CrossRefGoogle Scholar
  20. 20.
    Takahashi K, Wang F, Kantarjian H, Song X, Patel K, Neelapu S, et al. Copy number alterations detected as clonal hematopoiesis of indeterminate potential. Blood Adv. 2017;1(15):1031–6.CrossRefGoogle Scholar
  21. 21.
    Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87.CrossRefGoogle Scholar
  22. 22.
    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98.CrossRefGoogle Scholar
  23. 23.
    Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ, et al. Clonal dynamics of native haematopoiesis. Nature. 2014;514(7522):322–7.CrossRefGoogle Scholar
  24. 24.
    Boultwood J, Perry J, Zaman R, Fernandez-Santamaria C, Littlewood T, Kusec R, et al. High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression. Leukemia. 2010;24(6):1139–45.CrossRefGoogle Scholar
  25. 25.
    Kim T, Tyndel MS, Kim HJ, Ahn JS, Choi SH, Park HJ, et al. Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy. Blood. 2017;129(1):38–47.CrossRefGoogle Scholar
  26. 26.
    Roche-Lestienne C, Marceau A, Labis E, Nibourel O, Coiteux V, Guilhot J, et al. Mutation analysis of TET2, IDH1, IDH2 and ASXL1 in chronic myeloid leukemia. Leukemia. 2011;25(10):1661–4.CrossRefGoogle Scholar
  27. 27.
    Makishima H, Jankowska AM, McDevitt MA, O’Keefe C, Dujardin S, Cazzolli H, et al. CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia. Blood. 2011;117(21):e198–206.CrossRefGoogle Scholar
  28. 28.
    Kim T, Tyndel MS, Zhang Z, Ahn J, Choi S, Szardenings M, et al. Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy. Leuk Res. 2017;59:142–8.CrossRefGoogle Scholar
  29. 29.
    Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747–57.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  1. 1.Department of Medicine, Faculty of Medicine and Health Sciences (FMHS)Universiti Malaysia Sarawak (UNIMAS)Kota SamarahanMalaysia
  2. 2.Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences (IRCMS)Kumamoto UniversityKumamotoJapan
  3. 3.Department of Community Medicine and Public HealthFMHS, UNIMASKota SamarahanMalaysia
  4. 4.Department of PathologyFMHS, UNIMASKota SamarahanMalaysia
  5. 5.Department of Para-Clinical SciencesFMHS, UNIMASKota SamarahanMalaysia
  6. 6.Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore

Personalised recommendations