Транслокация t(1;11)(p32;q23) с образованием химерного гена MLL-EPS15 при острых лейкозах: обзор литературы и описание 6 новых случаев. Подходы к мониторированию минимальной остаточной болезни

На основании собственных исследований (6 пациентов) и данных литературы (27 случаев) представлена клинико-лабораторная характеристика острых лейкозов с транслокацией t(1;11)(p32;q23)/MLL-EPS15. Установлено, что наиболее часто транслокация t(1;11)(p32;q23) обнаруживается у детей первого года жизни (медиана возраста составляет 8 мес). При остром лимфобластном лейкозе лица мужского пола болеют реже (соотношение 1:3), при остром миелоидном лейкозе соотношение полов 1:1. Хромосомные аномалии, дополнительные к t(1;11)(p32;q23), выявлены в 38 % случаев. Наиболее часто зоной разрывов в ДНК гена EPS15 является интрон 1. Описано 4 типа химерных транскриптов MLL-EPS15. Создана и успешно применена комбинация праймеров, флуоресцентных зондов и плазмиды для мониторирования химерного транскрипта MLL-EPS15 методом полимеразной цепной реакции в режиме реального времени. Подобраны условия и проведен мониторинг минимальной остаточной болезни (МОБ) по индивидуальным точкам разрыва в геномной ДНК у пациентов с наличием химерного гена MLL-EPS15. Сравнение данных определения МОБ в геномной ДНК и кДНК показало высокую качественную сопоставимость результатов (92 %).

1. Armstrong S., Look A. Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 2005;23:6306–15.

2. Schoch C., Schnittger S., Klaus M. et al. AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic

3. impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 2003;102:2395–402.

4. Meyer С., Kowarz E., Hofmann J. et al. New insights to the MLL recombinome of acute leukemias. Leukemia 2009;23:1490–9.

5. Harrison C., Cuneo A., Clark R. et al. Ten novel 11q23 chromosomal partner sites. Leukemia 1998;12:811–22.

6. Williams D., Look A., Melvin S. et al. New chromosomal translocations correlate with specific lmmunophenotypes of childhood acute lymphoblastic leukemia. Cell 1984;36:101–9.

7. Kaneko Y., Maseki N., Takasaki N. et al. Clinical and hematologic characteristics in acute leukemia with 11q23 translocations. Blood 1986;67:484–91.

8. Gregoire M., Peeters M., Bene M. et al. K lymphoblastic leukemia. Haematol Blood Transfus 1987;30:504–8.

9. Selypes A., László A. A new translocation t(1;4;11) in congenital acute nonlymphocytic leukemia (acute myeloblastic leukemia). Hum Genet 1987;76:106–8.

10. Hagemeijer A., van Dongen J., Slater R. et al. Characterization of the blast cells in acute leukemia with translocation (4;11): report of eight additional cases and of one case with a variant translocation. Leukemia 1987;1:24–31.

11. Raimondi S., Peiper S., Kitchingman G. et al. Childhood acute lymphoblastic leukemia with chromosomal breakpoints at 11q23. Blood 1989;73:1627–34.

12. Shippey C., Lawlor E., Secker-Walker L. Isochromosome 9q in acute lymphoblastic leukemia: a new non-random finding. Leukemia 1989;3:195–9.

13. Abshire T., Buchanan G., Jackson J. et al. Morphologic, immunologic and cytogenetic studies in children with acute lymphoblastic leukemia at diagnosis and relapse: a Pediatric Oncology Group study. Leukemia 1992;6:357–62.

14. Bernard O., Mauchauffe M., Mecucci C. et al. A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL. Oncogene 1994;9: 1039–45.

15. Felix C., Hosler M., Slater D. et al. MLL genomic breakpoint distribution within the breakpoint cluster region in de novo leukemia in children. J Pediatr Hematol Oncol 1998;20:299–308.

16. Bergh von A., Emanuel B., Zelderen-Bhola van S. et al. A DNA probe combination for improved detection of MLL/11q23 breakpoints by double-color interphase-FISH in acute leukemias. Genes

17. Chromosomes and Cancer 2000;28:14–22.

18. Chessells J., Harrison C., Kempski H. et al. Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: report from the MRC Childhood Leukaemia working party.Leukemia 2002;16:776–84.

19. Park K., Lee D., Lee H. et al. Granulocytic Sarcoma in MLL-Positive Infant Acute Myelogenous Leukemia: Fluorescence in Situ Hybridization Study of Childhood Acute Myelogenous Leukemia for

20. Detecting MLL Rearrangement. Am J Pathol 2001;159(6):2011–6.

21. Kim H., Cho H., Kim E. et al. A study on 289 consecutive Korean patients with acute leukaemias revealed fluorescence in situ hybridization detects the MLL translocation without cytogenetic evidence both initially and during follow-up. Br J Haematol 2002;119(4):930–9.

22. Douet-Guilbert N., Morel F., Le Bris M. et al. Rearrangement of the MLL gene in acute myeloblastic leukemia: report of two rare translocations. Cancer Genet Cytogenet2005;157:169–74.

23. Sagawa M., Shimizu T., Shimizu T. et al. Establishment of a new human acute monocytic leukemia cell line TZ-1 with t(1;11)(p32;q23) and fusion gene MLLEPS15. Leukemia 2006;20:1566–71.

24. Kotecha R., Ford J., Beesley A. et al. Molecular characterization of identical, novel MLL-EPS15 translocation and individual genomic copy number alterations in monozygotic infant twins with acute

25. lymphoblastic leukemia. Haematologica 2012;97:1447–50.

26. Kotecha R., Murch A. Kees U., Cole C. Pre-natal, clonal origin of t(1;11)(p32;q23) acute lymphoblastic leukemia in monozygotic twins. Leuk Res 2012;36:46–50. 23. Nakamura H., Hata T., Tagawa M. et al. Chromosome 1 abnormalities at band 1p32in two atomic bomb survivors with myelodysplastic syndrome. Rinsho Ketsueki 2000;41:152–8.

27. http://www.genecards.org/cgi-bin/ carddisp.pl?gene=EPS15.25. http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000085832; r=1:51819935-51985000.

28. Su A., Wiltshire T., Batalov S. et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 2004;101:6062–7.

29. Salcini A., Chen H., Iannolo G. et al. Epidermal growth factor pathway substrate 15, Eps15. Int J Biochem Cell Biol 1999;31:805–9.

30. Parachoniak C., Park M. Distinct recruitment of Eps15 via its coiled-coil domain is required for efficient down-regulation of the MET receptor tyrosine kinase. J Biol Chem 2009;284(13):8382–94.

31. Hess J. MLL: a histone methyltransferase disrupted in leukemia. Trends in Molecular Medicine 2004;10(10):500–7.

32. Slany R. The molecular biology of mixed lineage leukemia. Haematol 2009;94:984–93.

33. Armstrong S., Staunton J., Silverman L. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002;30:41–7.

34. Ferrando A., Armstrong S., Neuberg D. et al. Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregu lation. Blood 2003;102:262–8.

35. Yeoh E., Ross M., Shurtleff S. et al. Classification, subtype discovery, and prediction of out-come in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 2002;1:133–43.

36. Ayton P., Cleary M. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes and Development 2003;17:2298–307.

37. Trentin L., Giordan M., Dingermann Th. et al. Two independent gene signatures in pediatric t(4;11) acute lymphoblastic leukemia patients. Euro J Haematol 2009;83:406–19.

38. Pallisgaard N., Hokland P., Riishoj D. et al. Multiplex reverse transcriptionpolymerase chain reaction for simultaneous screening of 29 translocations and chromosomal aberrations in acute leukemia. Blood 1998;92:574–88.

39. Dongen van J., Macintyre E., Gabert J. et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Leukemia 1999;13:1901–18.

40. Fechina L., Shorikov E., Tsaur G. et al. Contribution of all-trans retinoic acid to improved early relapse-free outcome in infant acute lymphoblastic leukemia comparing to the chemotherapy alone.

41. Blood 2007;110(11):832А; abstr. 2828.

42. ISCN 1995: An International System for Human Cytogenetic Nomenclature (1995). Ed. Mitelman F. Basel: S. Karger, 1995.

43. ISCN 2005: An International System For Human Cytogenetic Nomenclature (2005). Eds.: Shaffer L., Tommerup N. Basel: S. Karger, 2005.

44. ISCN 2009: An International System For Human Cytogenetic Nomenclature (2009). Eds.: Schaffer L., Slovak M., Campbell L. Basel: S. Karger, 2009.

45. Coenen E., Raimondi S., Harbott J. et al. Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL -rearranged AML patients: results of an international study. Blood 2011;117:7102–11.

46. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Eds.: Swerdlow S., Campo E., Harris N. et al. Lyon, France: IARC, 2008.

47. Betts D., Ammann R., Hirt A. et al. The prognostic significance of cytogenetic aberrations in childhood acute myeloid leukaemia. A study of the Swiss Paediatric Oncology Group (SPOG). Eur J Haematol 2007;78(6):468–76.

48. Meyer C., Schneider B., Reichel M. et al. Diagnostic tool for the identification of MLL rearrangements including unknown partner genes. Proc Natl Acad Sci USA2005;102(2):449–54.

49. Цаур Г.А., Наседкина Т.В., Попов А.М. и др. Время достижения молекулярной ремиссии как фактор прогноза у детей первого года жизни острым лимфобластным лейкозом. Онкогематол 2010;2:46–54.

50. Цаур Г.А., Друй А.Е., Попов А.М. и др. Возможность использования микроструйных биочипов для оценки качества и количества РНК у пациентов с онкологическими и онкогематологическими заболеваниями. Вестн Урал мед акад науки 2011;4:107–11.

51. Gabert J., Beillard E., Velden van der V. et al. 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 2003;17:2318–57.

52. Beillard E., Pallisgaard N., Velden van der V. et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe Against Cancer Program. Leukemia

53. ;17:2474–86.

54. Burmeister T., Marschalek R., Schneider B. et al. Monitoring minimal residual disease by quantification of genomic chromosomal breakpoint sequences in acute leukemias with MLL aberrations. Leukemia 2006;20:451–7.

55. Velden van der V., Cazzaniga G., Schrauder A. et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data.

56. Leukemia 2007;21:604–11.

57. Kaplan E., Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81.

58. Nilson I., Loechner K., Siegler G. et al. Exon/intron structure of ALL1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukemias. Br J Haematol 1996;94(4):966–72.

59. Mitelman database of chromosome aberrations and gene fusions in cancer (2012). Mitelman F., Johansson B. Mertens F. (eds.). http://cgap.nci.nih.gov/ Chromosomes/Mitelman.

60. Huret J.-L. t(1;11)(p32;q23). Atlas Genet Cytogenet Oncol Haematol (September 2010). http://

61. AtlasGeneticsOncology.org/Anomalies/t0111p32q23ID1046.html.

62. Chowdhury T., Brady H. Insights from clinical studies into the role of the MLL gene in infant and childhood leukemia. Blood Cells Mol Dis 2008;40:192–9.

63. Forestier E., Schmiegelow K. The incidence peaks of the childhood acute leukemias reflect specific cytogenetic aberrations. J Pediatr Hematol Oncol 2006;28:486–95.

64. Zweidler-McKay P., Hilden J. The ABCs of Infant Leukemia. Curr Probl Pediatr Adolesc Health Care 2008;38(3):78–94.

65. Цаур Г.А., Флейшман Е.В., Гиндина Т.Л. и др. Характеристика перестроек 11q23/MLL при остром миелоидном лейкозе у детей первого года жизни. Клин онкогематол 2012;5(4):365–71.

66. Цаур Г.А., Попов А.М., Алейникова О.В. и др. Характеристика перестроек 11q23 (MLL) у детей первого года жизни с острым лимфобластнымлейкозом. Онкогематол 2011;3:57–64.

67. Meyer C., Schneider B., Jakob S. et al. The MLL recombinome of acute leukemias. Leukemia 2006;20:777–84.

68. Цаур Г.А., Попов А.М., Наседкина Т.В. и др. Прогностическое значение минимальной остаточной болезни, определенной путем выявления химерных транскриптов у детей первого года жизни,

69. больных острым лимфобластным лейкозом, получающих терапию по протоколу MLL-BABY. Гематол и трансфузиол 2012;57(4):12–22.

70. Jansen M., Corral L., Velden van der V. et al. Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia 2007;21:633–41.

71. Peham M., Panzer S., Fasching K. et al. Low frequency of clonotypic Ig and T-cell receptor gene rearrangements in t(4;11) infant acute lymphoblastic leukaemia and its implication for the detection of minimal residual disease. Br J Haematol 2002;117:315–21.

72. De Zen L., Bicciato S., te Kronnie G., Basso G. Computational analysis of flowcytometry antigen expression profiles in childhood acute lymphoblastic leukemia: an MLL/AF4 identification. Leukemia

73. ;17:1557–65.

74. Schwartz S., Rieder H., Schlaeger B. et al. Expression of the human homologue of rat NG2 in adult acute lymphoblastic leukemia: close association with MLL rearrangement and a CD10(-)/CD24(-)/CD65s(+)/CD15(+) B-cell phenotype. Leukemia 2003;17:1589–95.

75. Attarbaschi A., Mann G., König M. et al. Mixed lineage leukemia-rearranged childhood pro-B and CD10-negative pre-B acute lymphoblastic leukemia constitute a distinct clinical entity. Clin Cancer Res 2006;12:2988–94.

76. Попов А.М., Вержбицкая Т.Ю., Цаур Г.А. и др. Особенности мониторинга минимальной остаточной болезни при B-линейных острых лимфобластных лейкозах методом проточной цитометрии у детей первого года жизни. Дет онкол 2008;2:32–5.

77. Попов А.М., Вержбицкая Т.Ю., Цаур Г.А. и др. Возможности применения NG2 для мониторинга минимальной остаточной болезни методом проточной цитометрии у детей первого года жизни

78. с острым лимфобластным лейкозом, ассоциированным с реарранжировками гена MLL. Гематол и трансфузиол 2009;6:19–22.

79. Velden van der V., Сorral L. Valsecchi M. et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant- 99 protocol. Leukemia 2009;23:1073–9.

80. Jansen M., Velden van der V., Dongen van J. Efficient and easy detection of MLL-AF4, MLL-AF9 and MLL-ENL fusion gene transcripts by multiplex real-time quantitative RT-PCR in TaqMan and

81. LightCycler. Leukemia 2005;19(11):2016–18.

82. Szczepanski T. Why and how to quantify minimal residual disease in acute lymphoblastic leukaemia. Leukemia 2007;21:622–6