Share This Article:

Frequency of Bcr-Abl Fusion Oncogene Splice Variants Associated with Chronic Myeloid Leukemia (CML)

Abstract Full-Text HTML Download Download as PDF (Size:159KB) PP. 176-180
DOI: 10.4236/jct.2011.22022    6,132 Downloads   12,289 Views   Citations

ABSTRACT

BCR-ABL fusion oncogene originates from the reciprocal translocation of chromosome 9 and 22 t(9;22) (q34;q11). It translates a chimeric protein, p210, characterized by constitutive activation of its tyrosine kinase, which triggers leukemogenic pathways resulting in onset of chronic myeloid leukemia (CML). In CML, the classic fusion is b2a2 or b3a2 fusing exon 13 (b2) or exon 14 (b3) of BCR to exon 2 (a2) of ABL. The type of bcr/abl transcripts may be associated with different prognosis and hence useful in therapeutic plan. This study was conducted to calculate the frequency of these splice variants as the frequencies of different fusion oncogenes associated with leukaemia can vary in different geographical regions due to interplay of genetic variation in different ethnic populations, diverse environmental factors and living style. A very sensitive nested RT-PCR was established to detect BCR-ABL splice variants in CML. Sensitivity of RT-PCR assay was of the order of 10–6. Thirty CML patients were subjected to BCR-ABL analysis. Out of 30 Pakistani patients, 19 (64%) expressed b3a2 while 11 (36%) expressed b2a2 transcript. This shows that BCR-ABL splice variants differ in their frequencies which may have an effect on biology and implications for prognosis and management of BCR-ABL positive Leukemias.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Z. Iqbal, F. Manzoor, M. Iqbal, S. Ali, N. Sheikh, M. Khan, A. Aleem and T. Akhtar, "Frequency of Bcr-Abl Fusion Oncogene Splice Variants Associated with Chronic Myeloid Leukemia (CML)," Journal of Cancer Therapy, Vol. 2 No. 2, 2011, pp. 176-180. doi: 10.4236/jct.2011.22022.

References

[1] Q. Cardama and J. E. Cortes, “Chronic Myeloid Leukemia: Diagnosis and Treatment,” Mayo Clinical Proceedings Journal, Vol. 81, No. 7, 2006, pp. 973-988.
[2] Y. Ben-Neriah, G. Q. Daley, A. M. Mes-Masson, O. N. Witte and D. Baltimore, “The Chronic Myelogenous Leukemia Specific P210 Protein is the Product of the Bcrabl Hybrid Gene,” Science, Vol. 233, No. 4760, 1986, pp. 212-214. doi:10.1126/science.3460176
[3] E. Shtivelman, B. Lifshitz, R. P. Gale and E. Canaani, “Fused Transcript of Abl and Bcr Genes in Chronic Myelogenous Leukaemia,” Nature, Vol. 315, No. 6020, 1985, pp. 550-554. doi:10.1038/315550a0
[4] R. M. Arana-Trejo, E. R. Sanchez, G. Ignacio-Ibarra, E. B. Fuente, O. Garces, E. G. Morales, M. C. Granados, R. O. Martinez, M. E. Rubio-Borja, L. S. Anaya, P. Herrera, J. D. Llamas and S. Kofman, “BCR/ABL P210, P190 and P230 Fusion Genes in 250 Mexican Patients with Chronic Myeloid Leukaemia,” (CML) Clinical Labortary Haem- otolgy, Vol. 24, No. 3, 2002, pp. 145-150. doi:10.1046/j.1365-2257.2002.00413.x
[5] B. D. Lichty, A. Keating, J. Callum, K. Yee, R. Croxford, G. Corpus, B. Nwachukwu, P. Kim, J. Guo and S. Kamel-Reid, “Expression of P210 and P190 BCR-ABL due to Alternative Splicing in Chronic Myelogenous Leukaemia,” British Journal of Haematology, Vol. 103, No. 3, 1998, pp. 711-715. doi:10.1046/j.1365-2141.1998.01033.x
[6] R. Ren, “Mechanisms of BCR-ABL in the Pathogenesis of Chronic Myelogenous Leukaemia,” Nature Review Cancer, Vol. 5, No. 3, 2005, pp. 172-183. doi:10.1038/nrc1567
[7] Z. Iqbal, A. Tanveer, et al, “First Comprehensive Report of Strong Interplay of Genetic and Environmental factors as well as High Degree of Ethnic and Geographical Variations in Biology of Leukemia as Manifested by Frequencies of Common Fusion Oncogenes of Prognostic Significance associated with Different Leukemic Subtypes in Pakistani population,” In: Online Proceedings of 100th Annual Meeting, American Association of Cancer Research, Colorado. October 2009.
[8] H. Ariffin, S. P. Chen, C. S. Kwok, T. C. Quah, H. P. Lin and A. E. Yeoh, “Ethnic Differences in the Frequency of Subtypes of Childhood Acute Lymphoblastic Leukemia: Results of the Malaysia-Singapore Leukemia Study Group,” Journal of Pediatric Hematology oncology, Vol. 29, No. 1, 2007, pp. 27-31. doi:10.1097/MPH.0b013e318030ac4c
[9] Z. Iqbal, “Frequency of Chromosomal Abnormalities and Corrresponding Fusion Oncogenes in Acute Lympoblastic Leukemia (ALL) Patients of Pakistan and Its Implication in Differential Diagnosis and Prognosis of Leukaemia,” Haematologica, Vol. 91, No. S3, 2006, p. 65.
[10] T. Hughes, M. Deininger, 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, Vol. 108, No. 1, 2006, pp. 28-37. doi:10.1182/blood-2006-01-0092
[11] P. Chomczynski and N. Sacchi, “Single Step Method of RNA Isolation by Acid Guanidinium Thiocyanate-Phenol- Chloroform Extraction,” Analytical of Biochemistry, Vol. 162, No. 1, 1987, pp. 156-159. doi:10.1016/0003-2697(87)90021-2
[12] P. Chomczynski, “A Reagent for the Single-Step Simultaneous Isolation of RNA, DNA and Proteins from Cell and Tissue Samples,” Biotechniques, Vol. 15, No. 3, 1993, pp. 532-537.
[13] J. A. Glasel, “Validity of Nucleic Acid Purities Monitored by A260/A280 Absorbance Ratios,” Biotechniques, Vol. 18, No. 1, 1995, pp. 62-63.
[14] J. Sambrook and W. D. Russel, “Molecular Cloning,” A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York, 2001.
[15] J. J. Van-Dongen, E. A. Macintyre, J. A. Gabert, E. Delabesse, V. Rossi, G. Saglio and E. Gottardi, “Standardized RT-PCR Analysis of Fusion Genes Transcripts from Chromosome Aberrations in Acute Leukemia for Detection of Minimal Residual Disease,” Report of the BIOMED-I Concerted Action: Investigation of Minimal Residual Disease in Acute Leukemia, Leukemia, Vol. 13, No. 12, 1999, pp. 1901-1928.
[16] J. P. Radich, G. Gehly, T. Gooley, E. Bryant, R. A. Clift, S. Collins, S. Edmands, J. Kirk, A. Lee and P. Kessler, “Polymerase Chain Reaction Detection of the BCR-ABL Fusion Transcript After Allogeneic Marrow Transplan- tation for Chronic Myeloid Leukemia: Results and Impli- cations in 346 Patients,” Blood, Vol. 85, No. 9, 1995, pp. 2632-2638.
[17] J. Q. Guo, H. Lin, H. Kantarjian, M. Talpaz, R. Champlin, M. Andreeff, A. Glassman and R. B. Arlinghaus, “Comparison of Competitive-Nested PCR and Real-Time PCR in Detecting BCR-ABL Fusion Transcripts in Chronic Myeloid Leukemia Patients,” Leukemia, Vol. 16, No. 12, 2002, pp. 2447-2453. doi:10.1038/sj.leu.2402730
[18] S. Menif, S. Zarrouki, R. Jeddi, N. ben Alaya, Z. B. Ali, H. B. Abid, S. Hdeiji, M. Elloumi, A. Khlif, B. Meddeb and K. Dellagi, “A Quantitative Detection of Bcr-Abl Transcripts in Chronic Myeloid Leukemia,” Pathologie Biologie, Vol. 57, No, 5, 2009, pp. 388-391. doi:10.1016/j.patbio.2007.12.010
[19] Z. Iqbal and A. Tanveer, “High Incidence of Bcr-Abl Fusion Oncogene in Pakistani Childhood Acute Lymp- hoid Leukaemia (ALL) Patients Reflects Ethnic Differences in Molecular Genetics of ALL,” Haematologica, Vol. 91, No. S3, 2006, p. 65.
[20] C. F. Verschraegen, H. M. Kantarjian, C. Hirsch-Ginsberg, M. S. Lee, S. O’Brien, M. B. Rios, S. A. Stass, M. Keating and M. Talpaz, “The Breakpoint Cluster Region Site in Patients with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia,” Clinical, Laboratory, and Prognostic Correlations, Cancer, Vol. 76, No. 6, 1995, pp. 992-997. doi:10.1002/1097-0142(19950915)76:6<992::AID-CNCR2820760612>3.0.CO;2-L
[21] E. Reiter, H. T. Greinix, S. Brugger, F. Keil, W. Rabitsch, C. Mannhalter, I. Schwarzinger, P. H?cker, G. Fischer, K. Dieckmann, W. Hinterberger, W. Linkesch, B. Schneider, K. Lechner and P. Kalhs, “Long-Term Follow-Up after allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia,” Bone Marrow Transplant, Vol. 22,No. S4, 1998, pp. S86-S88.
[22] H. G. Goh, J. Y. Hwang, S. H. Kim, Y. H. Lee, Y. L. Kim and D. W. Kim, “Comprehensive Analysis of BCR-ABL Transcript Types in Korean CML Patients Using a Newly Developed Multiplex RT-PCR,” Translational Research, Vol. 148, No. 1, 2006, pp. 249-256.
[23] M. Yaghmaie, S. H. Ghaffari, A. Ghavamzadeh, K. Alimoghaddam, M. Jahani, S. A. Mousavi, M. Irvani, B. Bahar and I. Bibordi, “Frequency of BCR-ABL Fusion Transcripts in Iranian Patients with Chronic Myeloid Leukemia,” Archives of Iranian Medicine, Vol. 11, No. 3, 2008, pp. 247-251.
[24] J. A. de Lemos, C. M. de Oliveira, A. C. Scerni, A. Q. Bentes, A. C. Beltr?o, I. R. Bentes, T. C. Azevedo, L. M. Maradei-Pereira, “Differential Molecular Response of the Transcripts B2A2 and B3A2 to Imatinib Mesylate in Chronic Myeloid Leukemia,” Genetics and Molecular Research, Vol. 4, No. 4, 30 December 2005, pp. 803-811.
[25] D. Verma, H. M. Kantarjian, D. Jones, R. Luthra, G. Borthakur, S. Verstovsek, M. B. Rios and J. Cortes, “Chronic Myeloid Leukemia (CML) with P190 BCR-ABL: Analysis of Characteristics, Outcomes, and Prognostic Significance,” Blood, Vol. 114, No. 11, 10 September 2009, pp. 2232-2235. doi:10.1182/blood-2009-02-204693
[26] P. Sharma, L. Kumar, S. Mohanty and V. Kochupillai, “Response to Imatinib Mesylate in Chronic Myeloid Leukemia Patients with Variant BCR-ABL fusion Transcripts,” Ann Hematology, Vol. 89, No. 3, March 2010, pp. 241-247. doi:10.1007/s00277-009-0822-7
[27] Z. Iqbal, M. Iqbal and T. Akhter, “Frequency of BCR-ABL Fusion Oncogene in Pakistani Childhood Acute Lymphoid Leukemia (ALL) Patients Reflects Ethnic Differences in Molecular Genetics of ALL,” Journal of Pediatric Hematology/Oncology, Vol. 29, No. 8, August 2007, p. 585. doi:10.1097/MPH.0b013e3180f61bcf
[28] F. X. Gruber, T. Lundán, R. Goll, A. Silye, I. Mikkola, O. P. Rekvig, S. Knuutila, K. Remes, T. Gedde-Dahl, K. Porkka and H. Hjorth-Hansen, “BCR-ABL Isoforms Associated with Intrinsic or Acquired Resistance to Imatinib: More Heterogeneous than just ABL Kinase Domain Point Mutations?” Medical Oncology, 8 January 2011.
[29] Z. Iqbal, M. Iqbal, M. Akhtar, M. I. Naqvi, A. H. Tahir, T. J. Gill, et al., “Presence of Prior-to-Treatment BCR-ABL Mutations In CD34 + CD38-Stem Cells of Newly Diagnosed Chronic Phase CML Patients and Their Correlation with Imatinib Resistance: Implications of Cancer Pharmacogenomics and Pre-Therapeutic Genetic Testing in Personalized Treatment of BCR-ABL+Leukemia Blood,” Vol. 116, No. 21, November 2010, p. 2278.
[30] C. M. Lucas, R. J. Harris, A. Giannoudis, A. Davies, K. Knight, S. J. Watmough, L. Wang, R. E. Clark, “Chronic Myeloid Leukemia Patients with the E13a2 BCR-ABL Fusion Transcript have Inferior Responses to Imatinib Compared to Patients with the E14a2 Transcript,” Haematologica, Vol. 94, No. 10, October 2009, pp. 1362-1367. doi:10.3324/haematol.2009.009134

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.