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KIT Proto-oncogene Exon 8 Deletions at Codon 419 are Highly Frequent in Acute Myeloid Leukaemia with Inv(16) in Indian Population

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Abstract

The KIT gene is a receptor tyrosine kinase class III expressed by early hematopoietic progenitor cells and plays a significant role in hematopoietic stem cell proliferation, differentiation and survival which is considered to be a remarkable feature in the course of growth of acute myeloid leukaemia (AML). Owing to insufficient study of mutations in the KIT gene, the diagnosis and rate of recurrence of these mutations with divergent subtypes in AML cases in India is of concern. In order to find out the frequency of mutations of KIT gene exon 8 in 109 AML cases, we have performed polymerase chain reaction–single-strand conformation polymorphism (PCR–SSCP) followed by DNA sequencing and have identified 24 mutations in exon 8 in 13 cases, including deletions at codon 418 (n = 3), 419 (n = 11) and 420 (n = 5) as well as point mutations at codon 417 (n = 1) and 421 (n = 4). In eleven AML cases, exon 8 deletion and point mutations involved the loss at codon Asp419 immoderately conserved cross species placed in the receptor extracellular domain. Frequency elevation of the KIT proto-oncogene exon 8 deletion and point mutations in AML cases allude a crucial function for this region of the receptor extracellular domain. Thus, we report the incidence of acquired mutations in exon 8, with consistent loss at codon Asp419, in 10.09 % of AML cases in a selected Indian population.

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References

  1. Mecucci, C., Rosati, R., & La Starza, R. (2002). Genetic profile of acute myeloid leukemia. Reviews in Clinical & Experimental Hematology, 61, 3–25.

    Google Scholar 

  2. Speck, N. A., & Gilliland, D. G. (2002). Core-binding factors in haematopoiesis and leukaemia. Nature Reviews, 2, 502–513.

    Article  CAS  Google Scholar 

  3. Wakita, S., Yamaguchi, H., Miyake, K., Mitamura, Y., Kosaka, F., Dan, K., et al. (2011). Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia. Leukemia, 25, 1423–1432.

    Article  CAS  Google Scholar 

  4. Shurtleff, S. A., Meyers, S., Hiebert, S. W., Raimondi, S. C., Head, D. R., Willman, C. L., et al. (1995). Heterogeneity in CBF beta/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16;16)(p13;q22) in acute myelogenous leukemia. Blood, 85, 3695–3703.

    CAS  Google Scholar 

  5. Fröhling, S., Skelin, S., Liebisch, C., Scholl, C., Schlenk, R. F., Döhner, H., et al. (2002). Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia. Journal Clinical Oncology, 20, 2480–2485.

    Article  Google Scholar 

  6. Liu, P., Tarle, S. A., Hajra, A., Claxton, D. F., Marlton, P., Freedman, M., et al. (1993). Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science, 261, 1041–1044.

    Article  CAS  Google Scholar 

  7. Care, R. S., Valk, P. J., Goodeve, A. C., Abu-Duhier, F. M., Geertsma-Kleinekoort, W. M., Wilson, G. A., et al. (2003). Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. British Journal of Haematology, 121, 775–777.

    Article  CAS  Google Scholar 

  8. Gilliland, D. G. (2001). Hematologic malignancies. Current Opinions in Haematology, 8, 189–191.

    Article  CAS  Google Scholar 

  9. Vliagoftis, H., Worobec, A. S., & Metcalfe, D. D. (1997). The proto-oncogene c-kit and c-kit ligand in human disease. Journal of Allergy and Clinical Immunology, 100, 435–440.

    Article  CAS  Google Scholar 

  10. Vandenbark, G. R., deCastro, C. M., Taylor, H., Dew-Knight, S., & Kaufman, R. E. (1992). Cloning and structural analysis of the human c-kit gene. Oncogene, 7, 1259–1266.

    CAS  Google Scholar 

  11. Yarden, Y., Kuang, W. J., Yang-Feng, T., Coussens, L., Munemitsu, S., Dull, T. J., et al. (1987). Human proto-oncogene c-kit: A new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO Journal, 6, 3341–3351.

    CAS  Google Scholar 

  12. Paschka, P., Marcucci, G., Ruppert, A. S., Mrózek, K., Chen, H., Kittles, R. A., et al. (2006). Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): A Cancer and Leukemia Group B Study. Journal Clinical Oncology, 24, 3904–3911.

    Article  CAS  Google Scholar 

  13. d’Auriol, L., Mattei, M. G., Andre, C., & Galibert, F. (1988). Localization of the human c-kit protooncogene on the q11–q12 region of chromosome 4. Human Genetics, 78, 374–376.

    Article  Google Scholar 

  14. Renneville, A., Roumier, C., Biggio, V., Nibourel, O., Boissel, N., Fenaux, P., et al. (2008). Cooperating gene mutations in acute myeloid leukemia: A review of the literature. Leukemia, 22, 915–931.

    Article  CAS  Google Scholar 

  15. Reilly, J. T. (2002). Class III receptor tyrosine kinases: Role in leukaemogenesis. British Journal of Haematology, 116, 744–757.

    Article  CAS  Google Scholar 

  16. Zaker, F., Mohammadzadeh, M., & Mohammadi, M. (2010). Detection of KIT and FLT3 mutations in acute myeloid leukemia with different subtypes. Archives of Iranian Medicine, 13, 21–25.

    CAS  Google Scholar 

  17. Gari, M., Goodeve, A., Wilson, G., Winship, P., Langabeer, S., Linch, D., et al. (1999). C-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. British Journal of Haematology, 105, 894–900.

    Article  CAS  Google Scholar 

  18. Kohl, T. M. K., Susanne, S., Ellwart, J. W., Wolfgang, H., & Karsten, S. (2005). KIT exon 8 mutations associated with core-binding factor (CBF)–acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. Blood, 105, 3319–3321.

    Article  CAS  Google Scholar 

  19. Wang, Y.- Y., Zhou, G.-B., Yin, T., Chen, B., Shi, J.-Y., Liang, W.-X., et al. (2005). AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: Implication in stepwise leukemogenesis and response to Gleevec. PNAS, 102, 1104–1109.

    Article  CAS  Google Scholar 

  20. Cole, S. R., Aylett, G. W., Harvey, N. L., Cambareri, A. C., & Ashman, L. K. (1996). Increased expression of c-Kit or its ligand steel factor is not a common feature of adult acute myeloid leukaemia. Leukemia, 10, 288–296.

    CAS  Google Scholar 

  21. Beghini, A. P., Peterlongo, C. B., Ripamonti, L., Larizza, R., & Cairoli, E. (2000). C-KIT mutation in core binding factor leukemias. Blood, 95, 726–727.

    CAS  Google Scholar 

  22. Pardanani, A., & Tefferi, A. (2004). Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Blood, 104, 1931–1939.

    Article  CAS  Google Scholar 

  23. Higuchi, M., O’Brien, D., Kumaravelu, P., Lenny, N., teoh, E. J., & Downing, J. R. (2002). Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell, 1, 63–74.

    Article  CAS  Google Scholar 

  24. Jemal, A., Thomas, A., Murray, T., & Thun, M. (2002). Cancer statistics 2002. CA: A Cancer Journal for Clinicians, 52, 23–47.

    Article  Google Scholar 

  25. Nanri, T., Matsuno, N., Kawakita, T., Suzushima, H., Kawano, F., Mitsuya, H., et al. (2005). Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22; q22). Leukemia, 19, 1361–1366.

    Article  CAS  Google Scholar 

  26. Wang, Y. Y., Zhou, G. B., Yin, T., Chen, B., Shi, J. Y., Liang, W. X., et al. (2005). AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: Implication in stepwise leukemogenesis and response to Gleevec. Proceedings of the National Academy of Sciences of the United States of America, 102, 1104–1109.

    Article  CAS  Google Scholar 

  27. Schnittger, S., Kohl, T. M., Haferlach, T., Kern, W., Hiddemann, W., Spiekermann, K., et al. (2006). KITD816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood, 107, 1791–1799.

    Article  CAS  Google Scholar 

  28. Cairoli, R., Beghini, A., Grillo, G., Nadal, G., Elice, F., Ripamonti, C. B., et al. (2006). Prognostic impact of c-KIT mutations in core binding factor leukemias: An Italian retrospective study. Blood, 107, 3463–3468.

    Article  CAS  Google Scholar 

  29. Boissel, N., Leroy, H., Brethon, B., Philippe, N., de Botton, S., Auvrignon, A., et al. (2006). Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia, 20, 965–970.

    Article  CAS  Google Scholar 

  30. Park, S. H., Chi, H. S., Min, S. K., Park, B. G., Jang, S., & Park, C. J. (2011). Prognostic impact of c-KIT mutations in core binding factor acute myeloid leukemia. Leukemia Research, 35, 1376–1383.

    Article  CAS  Google Scholar 

  31. Yuan, Y., Zhou, L., Miyamoto, T., Iwasaki, H., Harakawa, N., Hetherington, C. J., et al. (2001). AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proceedings of the National academy of Sciences of the United States of America, 98, 10398–10403.

    Article  CAS  Google Scholar 

  32. Beghini, A., Cairoli, R., Morra, E., & Larizza, L. (1998). In vivo differentiation of mast cells from acute myeloid leukemia blasts carrying a novel activating ligand-independent c-kit mutation. Blood Cells, Molecules, & Diseases, 24, 262–270.

    Article  CAS  Google Scholar 

  33. Beghini, A., Magnani, I., Ripamonti, C. B., & Larizza, L. (2002). Amplification of a novel c-kit activating mutation Asn(822)-Lys in the Kasumi-1 cell line: A t(8;21)-kit mutant model for acute myeloid leukemia. Haematology Journal, 3, 57–63.

    Google Scholar 

  34. Beghini, A., Ripamonti, C. B., Castorina, P., Pezzetti, L., Doneda, L., Cairoli, R., et al. (2000). Trisomy 4 leading to duplication of a mutated KIT allele in acute myeloid leukemia with mast cell involvement. Cancer Genetics and Cytogenetics, 119, 26–31.

    Article  CAS  Google Scholar 

  35. Bo¨ll, I., Schoch, C., Haferlach, T., Hiddemann, W., & Schnittger, S. (2002). Not only c-KIT exon 8-, but also NRAS- and FLT3D835-mutations are frequent molecular alterations in patients with acute myeloid leukemia M4eo and inv(16). Blood, 100, 746a.

    Google Scholar 

  36. Goemans, B. F., Zwaan, C. M., Miller, M., Zimmermann, M., Hahlen, K., Reinhardt, D., et al. (2003). Incidence and prognostic significance of c-kit exon 8 and 17 mutations in pediatric acute myeloid leukemia (AML). Blood, 102, 198b.

    Google Scholar 

  37. Bennett, J. M., Catovsky, D., Daniel, M. T., Flandrin, G., Galton, D. A., Gralnick, H. R., et al. (1976). Proposal for the classification of the acute leukaemias. French American British (FAB) cooperative group. British Journal of Haematology, 33, 451–458.

    Article  CAS  Google Scholar 

  38. ISCN (International System for Human Cytogenetic Nomenclature). (1991). Guidelines for cancer cytogenetics. In: F. Mitelman (Ed.) Supplement to an international system for human cytogenetic nomenclature (pp. 1–53). Basel: Karger.

  39. Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K., & Sekiya, T. (1989). Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphism. Proceedings of the National academy of Sciences of the United States of America, 86, 2766–2770.

    Article  CAS  Google Scholar 

  40. http://www.mbio.ncsu.edu/bioedit/bioedit.html. Accessed 14 June 2012.

  41. http://en.bio-soft.net/dna/FinchTV.html. Accessed 14 June 2012.

  42. http://www.justbio.com/index.php?page=primer. Accessed 14 June 2012.

  43. Hussain, S. R., Ahmed, F., Naqvi, H., Singh, P., Mahdi, F., & Babu, S. G. (2009). C-kit proto-oncogene deletion and point mutation at exon 8, 17 in human acute myeloid leukemia. Turkish Journal of Cancer, 39, 95–103.

    Google Scholar 

  44. Castilla, L., Garrett, L., Adya, N., Orlic, D., Dutra, A., Anderson, S., et al. (1999). The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nature Genetics, 23, 144–146.

    Article  CAS  Google Scholar 

  45. Abu-Duhier, F. M., Goodeve, A. C., Wilson, G. A., Peake, I. R., & Reilly, J. T. (2003). Mutational analysis of c-FMS in acute myeloid leukaemia. British Journal of Haematology, 123, 749–750.

    Article  Google Scholar 

  46. Broudy, V. C., Lin, N. L., & Sabath, D. F. (2001). The fifth immunoglobulin-like domain of the kit receptor is required for proteolytic cleavage from the cell surface. Cytokine, 15, 188–195.

    Article  CAS  Google Scholar 

  47. Beghini, A., Ripamonti, B. C., Cairoli, R., Cazzaniga, G., Colapietro, P., Elice, F., et al. (2004). KIT activating mutations: Incidence in adult and pediatric acute myeloid leukemia, and identification of an internal tandem duplication. Haematologica, 89, 920–925.

    CAS  Google Scholar 

  48. http://www.igdd.iicb.res.in/IGDD/home.aspx. Accessed 14 June 2012.

  49. Mrozek, K., & Bloomfield, C. D. (2006). Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. American Society of Hematology Education Program, 2006, 169–177.

    Article  Google Scholar 

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Acknowledgments

A major part of this study was supported by intramural grant from the Era’s Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India. We gratefully acknowledge the technical support by Dr. Mohammad Imran Siddiqui, Molecular and Structural Biology Division, Central Drug Research Institute (CDRI-CSIR), Lucknow, India.

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Authors and Affiliations

  1. Molecular Biology Lab, Department of Biotechnology, Era’s Lucknow Medical College and Hospital, Lucknow, 226003, Uttar Pradesh, India

    Syed Rizwan Hussain & Hena Naqvi

  2. Department of Pathology, Era’s Lucknow Medical College and Hospital, Lucknow, 226003, Uttar Pradesh, India

    Cherry Bansal

  3. Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, 226025, Uttar Pradesh, India

    Sunil G. Babu

  4. Department of Biochemistry, Era’s Lucknow Medical College and Hospital, Lucknow, 226003, Uttar Pradesh, India

    Farzana Mahdi

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  1. Syed Rizwan Hussain
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Correspondence to Sunil G. Babu.

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Hussain, S.R., Naqvi, H., Mahdi, F. et al. KIT Proto-oncogene Exon 8 Deletions at Codon 419 are Highly Frequent in Acute Myeloid Leukaemia with Inv(16) in Indian Population. Mol Biotechnol 54, 461–468 (2013). https://doi.org/10.1007/s12033-012-9584-x

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