medigraphic.com
ISSN 1561-2996 (Electronic)
ISSN 0864-0289 (Print)

2018, Number 3

<< Back Next >>

Rev Cubana Hematol Inmunol Hemoter 2018; 34 (3)

Characterization of RUNX1-RUNX1T1 fusion gene in Cuban patients with acute myeloid leukemia, 2000-2016

Garrote SH, Amor VAM, Díaz ACA, Fernández ML, Ruiz MV, Machín GS, Bencomo HA

Language: Spanish
References: 60
Page: 1-16
PDF size: 378.97 Kb.


ABSTRACT

Introduction: The RUNX1-RUNX1T fusion gene codes for a chimeric protein with multiple effects on the proliferation, differentiation and viability of leukemic cells.
Objective: To describe the behavior of RUNX1-RUNX1T1 in Cuban patients with this disease.
Method: The RUNX1-RUNX1T1 fusion gene was studied in 251 patients with acute myeloid leukemia, through the polymerase chain reaction, at the Institute of Hematology and Immunology of Havana, between 2000 and 2016.
Results: The 20.3 % (51 patients) were positive for the RUNX1-RUNX1T1 fusion gene, with an age between 11 months and 80 years, average of 26 years.In pediatric patients, the transcript frequency was almost twice that of adults (29.2 % and 15.3 %, respectively) (p= 0.009). More male patients presented the chimeric gene. There was a higher frequency of the transcript in children under 25 years of age (p= 0.019) with a significant predominance of the mutation in adolescents (p= 0.027).Five patients were positive for RUNX1-RUNX1T1 and for internal tandem duplication of the FLT3 gene (12.2 %).No patient positive for RUNX1-RUNX1T1 presented the CBFB-MYH11 fusion gene. The greatest association was with the A mutation of the NPM1 gene for 25 %. The onset of the disease was characterized by moderate anemia (p= 0.024), severe thrombocytopenia (p= 0.004) and extensive bone marrow infiltration. The greatest discrepancy between diagnoses was concentrated between the morphological variants M2 and M3 (p= 0.000).
Conclusions: In Cuban patients, acute myeloid leukemia with a positive RUNX1-RUNX1T1 fusion gene has a behavior similar to that described internationally with some peculiarities in the hematological characteristics of the disease presentation.The molecular study is essential to define the diagnosis, and the therapeutic strategy in these patients.


REFERENCES

  1. Kaushansky K, Lichtman MA, Prchal J, Levi MM, Press O, Burns L, et al. Acute Myelogenous Leukemia. In: William´s Hematology. 9th Ed. New York: McGraw-Hill; 2016.

  2. Emadi A, Baer MR. Acute Myeloid Leukemia in Adults. In: Wintrobe's Clinical Hematology. 13th Ed. Philadelphia: Lippincott Williams & Wilkins. 2014. p. 1577-615.

  3. Arceci RJ. Acute Myelogenous Leukemia in Children. In: Wintrobe's Clinical Hematology. 13th Ed. Philadelphia: Lippincott Williams & Wilkins. 2014. p. 1637-55.

  4. Garrote Santana H, Lavaut Sánchez K, Amor Vigil AM, Díaz Alonso C, Fernández Martínez L, Ruiz MoleónV, et al. Cinco décadas de la biología molecular y la citogenética aplicadas a la hematología cubana. Rev Cubana Hematol Inmunol Hemoter [Internet]. 2017 Mar [citado 2018 Ene 19];33(1):1-8. Disponible en: http://scielo.sld.cu/scielo.php?script=sci_arttext&pid=S0864- 02892017000100004&lng=es

  5. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976 Aug;33(4):451-8.

  6. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405.

  7. Yohe S. Molecular Genetic Markers in Acute Myeloid Leukemia. J Clin Med. 2015 Mar;4(3):460-78.

  8. Manivannan P, Puri V, Somasundaram V, Purohit A, Sharma RK, Dabas M, et al. Can threshold for MPO by flow cytometry be reduced in classifying acute leukaemia? A comparison of flow cytometric and cytochemical myeloperoxidase using different flow cytometric cut-offs. Hematology. 2015;20(8):455-61.

  9. Wang X. Advances and issues in flow cytometric detection of immunophenotypic changes and genomic rearrangements in acute pediatric leukemia. Transl Pediatr 2014;3(2):149-55.

  10. Soriano I, Vásquez E, Niquén S, Fernández M, Castañeda K, Fernández J. Caracterización inmunofenotípica de leucemias agudas diagnosticadas en un Hospital Nivel III en el periodo 2010-2013, Chiclayo-Perú. Rev Cuerpo Méd HNAAA. 2015;8(1):5-9.

  11. Hu L, Ru K, Zhang L, Huang Y, Zhu X, Liu H, et al. Fluorescence in situ hybridization (FISH): an increasingly demanded tool for biomarker research and personalized medicine. Biomark Res. 2014 Feb 5;2(1):3.

  12. van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999 Dec;13(12):1901-28.

  13. Luthra R, Patel KP, Reddy NG, Haghshenas V, Routbort MJ, Harmon MA, et al. Nextgeneration sequencing-based multigene mutational screening for acute myeloid leukemia using MiSeq: applicability for diagnostics and disease monitoring. Haematologica. 2014 Mar;99(3):465-73.

  14. Swerdlow SH, Campo E, Pileri SA, Lee Harris N, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19;127(20):2375-90.

  15. Soares Almeida AL, Campos de Azevedo I, de Souza Rego Pinto Carvalho DP, Fortes Vitor A, Pereira Santos VE, Ferreira Jr MA. Clinical and epidemiological aspects of leukemias. Rev Cubana Hematol Inmunol Hemoter [Internet]. 2017 Jun [citado 2017 Ago 8];33(2):1-14. Disponible en: http://scielo.sld.cu/scielo.php?script=sci_arttext&pid=S0864- 02892017000200006&lng=es

  16. Rowley JD. Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet.1973;16(2):109-12.

  17. Duployez N, Marceau-Renaut A, Boissel N, Petit A, Bucci M, Geffroy S, et al. Comprehensive mutational profiling of core binding factor acute myeloid leukemia. Blood. 2016 May;127(20):2451-9.

  18. Reikvam H, Hatfield KJ, Kittang AO, Hovland R, Bruserud O. Acute myeloid leukemia with the t(8;21) translocation: clinical consequences and biological implications. J Biomed Biotechnol. 2011;2011:1-23.

  19. Sakurai M, Kunimoto H, Watanabe N, Fukuchi Y, Yuasa S, Yamazaki S, et al. Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients. Leukemia. 2014;28:2344-54.

  20. Garrote H, Amor AM, Díaz CA, Suárez Y, Arencibia A. Runx1-Runx1t1: comportamiento en pacientes con leucemia mieloide aguda en nuestro medio. Rev Cubana de Hematol Inmunol Hemoter. 2015;31(4):417-25.

  21. Bidet A, Laharanne E, Achard S, Migeon M, Moreau C, Lippert E, et al. Analysis of RUNX1 rearrangements: insights into leukaemogenesis mechanisms. Br J Haematol. 2016 Nov;175(4):738-40.

  22. Conway E, Prideaux E, Chevassut T. The Epigenetic Landscape of Acute Myeloid Leukemia. Adv Hematol. 2014 Mar;23:1-15.

  23. Antony-Debré I , Manchev VT, Balayn N , Bluteau D , Tomowiak C , Legrand C , et al. Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. Blood. 2015 Feb;125(6):930-40.

  24. Rodriguez-Perales S, Torres-Ruiz R, Suela J, Acquadro F, Martin MC, Yebra E, et al. Truncated RUNX1 protein generated by a novel t(1;21)(p32;q22) chromosomal translocation impairs the proliferation and differentiation of human hematopoietic progenitors. Oncogene. 2016 Jan;35(1):125-34.

  25. Garrote H, Amor AM, Díaz CA, Suárez Y, Gómez M. Gen de fusión AML1-ETO: particularidades en la leucemia mieloide aguda. Rev Cubana Hematol Inmunol Hemoter. 2014;30(2):98-107.

  26. Fernández L. Consideraciones sobre la fase preanalítica en los estudios moleculares de las hemopatías malignas. Rev Cubana Hematol Inmunol Hemoter [Internet]. 2017 Jun [citado 2018 Ene 19];33(2):1-4. Disponible en: http://scielo.sld.cu/scielo.php?script=sci_arttext&pid=S0864- 02892017000200013&lng=es

  27. Díaz C, Garrote H, Amor AM, Suárez Y, González R. Cuantificación de ácido ribonucleico para la realización de la técnica de RT- PCR. Rev Cubana Hematol Inmunol Hemoter. 2013 Sep;29(3):298-303.

  28. Díaz C, Garrote H, Amor AM, Suárez Y, Fernández L, Ruiz V. Nuevos métodos de extracción de ácidos ribonucleicos (ARN): herramientas básicas en la biología molecular. Rev Cubana Hematol Inmunol Hemoter[revista en Internet]. 2015 [citado 2017 Ago 8];31(4):[aprox. 0 p.]. Disponible en: http://www.revhematologia.sld.cu/index.php/hih/article/view/349

  29. Maniatis T, Fritsch EF, Sambrook J. Molecular cloning. In: Laboratory Manual. 1st Ed. New York: Cold Spring Harbor Laboratory; 1982.

  30. Nakao M, Iwai T, Kaneko H, Horiike S, Kashima K, Sonoda Y, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996 Dec;10(12):1911-8.

  31. Ottone T, Ammatuna E, Lavorgna S, Noguera NI, Buccisano F, Vendittiet A, et al. An allelespecific RT-PCR assay to detect type A mutation of the nucleophosmin-1 gene in acute myeloid leukemia. J Mol Diagnostics. 2008 May;10(3):212-6.

  32. Ruiz V, Garrote H, Díaz CA, Fernández L, Amor AM. Electroforesis capilar: nueva técnica en el Instituto de Hematología e Inmunología para el análisis de marcadores oncohematológicos. Rev Cubana Hematol Inmunol Hemoter [revista en Internet]. 2017 [citado 2018 Ene 19];33(3):[aprox. 0 p.]. Disponible en: http://www.revhematologia.sld.cu/index.php/hih/article/view/538

  33. World Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310(20):2191-4.

  34. Krauth MT, Eder C, Alpermann T, Bacher U, Nadarajah N, Kern W, et al. High number of additional genetic lesions in acute myeloid leukemia with t(8;21)/RUNX1-RUNX1T1: frequency and impact on clinical outcome. Leukemia. 2014 Jul;28(7):1449-58.

  35. Shiba N, Yoshida K, Shiraishi Y, Okuno Y, Yamato G, Hara Y, et al. Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. Br J Haematol. 2016 Nov;175(3):476-89.

  36. Sanz MA, Carreras E. Manual Práctico de Hematología Clínica. 5ta ed. Molins de Rei: Antares; 2015.

  37. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010 Jul;116(3):354-65.

  38. Kihara R, Nagata Y, Kiyoi H, Kato T, Yamamoto E, Suzuki K, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia. 2014 Aug;28(8):1586-95.

  39. 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.

  40. Genovese G, Jaiswal S, Ebert BL, McCarroll SA. Clonal hematopoiesis and blood-cancer risk. N Engl J Med. 2015 Mar;372(11):1071-2.

  41. Scherer F, Kurtz DM, Diehn M, Alizadeh AA. High-throughput sequencing for noninvasive disease detection in hematologic malignancies. Blood. 2017 Jul;130(4):440-52.

  42. Gaidzik VI, Teleanu V, Papaemmanuil E, Weber D, Paschka P, Hahn J. RUNX1 mutations in acute myeloid leukemia are associated with distinct clinic-pathologic and genetic features. Leukemia. 2016;30:2160-8.

  43. Wiemels JL, Xiao Z, Buffler PA, Maia AT, Ma X, Dicks BM, et al. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood. 2002 May;99(10):3801-5.

  44. Lafiura KM, Bielawski DM, Posecion NC Jr, Ostrea EM Jr, Matherly LH, Taub JW, et al. Association between prenatal pesticide exposures and the generation of leukemia-associated T(8;21). Pediatr Blood Cancer. 2007 Oct49(5):624-8.

  45. Minucci S. DNA binding modes of leukemia oncoproteins. Blood. 2016 Jan;127(2):177-8.

  46. Li Y, Wang H, Wang X, Jin W, Tan Y, Fang H, et al. Genome-wide studies identify a novel interplay between AML1 and AML1/ETO in t(8;21) acute myeloid leukemia. Blood. 2016 Jan;127(2):233-42.

  47. Qin YZ, Wang Y, Xu LP, Zhang XH, Chen H, Han W, et al. The dynamics of RUNX1- RUNX1T1 transcript levels after allogeneic hematopoietic stem cell transplantation predict relapse in patients with t(8;21) acute myeloid leukemia. J Hematol Oncol. 2017 Feb;10(1):44.

  48. Medinger M, Passweg JR. Acute myeloid leukaemia genomics. Br J Haematol. 2017 Nov;179(4):530-42.

  49. Falini B, Sportoletti P, Brunetti L, Martelli MP. Perspectives for therapeutic targeting of gene mutations in acute myeloid leukaemia with normal cytogenetics. Br J Haematol. 2015 Aug;170(3):305-22.

  50. Qin YZ, Zhu HH, Jiang Q, Jiang H, Zhang LP, Xu LP, et al. Prevalence and prognostic significance of c-KIT mutations in core binding factor acute myeloid leukemia: a comprehensive large-scale study from a single Chinese center. Leuk Res. 2014 Dec;38(12):1435-40.

  51. Sood R, Kamikubo Y, Liu P. Role of RUNX1 in hematological malignancies. Blood. 2017 April;129(15):2070-81.

  52. Wang M, Yang C, Zhang L, Schaar DG. Molecular mutations and their co-occurrences in cytogenetically normal Acute Myeloid Leukemia. Stem Cells International. 2017; 2017:1-11.

  53. Amor-Vigil AM, Díaz-Alonso CA, Hernández-Cabezas A, Marsán-Suárez V, Garrote- Santana H, Espinosa-Martínez E. Gen de fusión AML-1/ETO y mutación NPM-1A en leucemia mieloide crónica en crisis blástica mieloide. Rev Cubana Hematol Inmunol Hemoter [Internet]. 2015 Mar [citado 2017 Ago 8];31(1):71-78. Disponible en: http://scielo.sld.cu/scielo.php?script=sci_arttext&pid=S0864-02892015000100009&lng=es

  54. Balatzenko G, Spassov B, Stoyanov N, Ganeva P, Dikov T, Konstantinov S, et al. NPM1 Gene Type A Mutation in Bulgarian Adults with Acute Myeloid Leukemia: A Single-Institution Study. Turk J Hematol. 2014 Mar;31(1):40-8.

  55. Papaemmanuil E, Döhner H, Campbell PJ. Genomic Classification in Acute Myeloid Leukemia. N Engl J Med. 2016 Sep;375(9):900-1.

  56. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and Management of AML in Adults: 2017 ELN Recommendations from an International Expert Panel. Blood. Blood. 2017 Jan;129(4):42447.

  57. Prabahran AA, Tacey M, Fleming S, Strong D, Wei A, Tate C, et al. Prognostic Markers in Core-Binding Factor Acute Myeloid Leukaemia. Blood. 2015;126:25-99.

  58. Liersch R, Müller-Tidow C, Berdel WE, Krug U. Prognostic factors for acute myeloid leukaemia in adults - biological significance and clinical use. Br J Haematol. 2014 Apr;165(1):17-38.

  59. Shin HJ, Chung J, Kim HJ, Sohn SK, MinYH, Won JH et al. Bone marrow cellularity is a single most important independent prognostic factor in AML patients with t(8;21). Blood. 2010;116(21):1707.

  60. Gritsaev SV, Martynkevich IS, Ziuzgin IS, Kariagina EV, Martynenko LS, Petrova EV, et al. Heterogeneity of acute myeloid leukemia with the translocation t(8;21)(q22;q22). TerArkh. 2014; 86(7):45-52.




2020     |     www.medigraphic.com