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Mosaiktrisomie 8p11.21q11.21 als Prädisposition für myeloische Leukämien

Mosaic trisomy 8p11.21q11.21 predisposing to myeloid leukemia

Zusammenfassung

Bei der juvenilen myelomonozytären Leukämie (JMML) handelt es sich um eine myeloproliferative Erkrankung der frühen Kindheit. Bei vielen Patienten lassen sich zugrunde liegende somatische, aber auch konstitutionelle Mutationen in NRAS, KRAS, PTPN11, NF1 und CBL nachweisen. Zur Identifizierung submikroskopischer Veränderungen, die für die leukämische Transformation von Bedeutung sein können, wurden 20 JMML-Proben mittels hochauflösender Oligo-Microarray-basierter komparativer genomischer Hybridisierung (aCGH) untersucht. Bei 2 von 10 Patienten mit submikroskopischen Aberrationen konnte ein nahezu identischer Zugewinn von Chromosom 8 gezeigt werden, der sich in weiteren Untersuchungen als konstitutionelles Mosaik darstellte. Eine Übersicht von 27 Patienten mit einem konstitutionellen Trisomie-8-Mosaik (cT8M) und maligner Neoplasie zeigte, dass es sich meist um myeloische Neoplasien, auch JMML, handelt. Durch unsere Untersuchungen konnte die kritische Region auf Chromosom 8, deren Loci mutmaßlich an der Leukämieentstehung und/oder Progression beteiligt sein können, dramatisch reduziert werden: 8p11.21q11.21. Es bleibt zu klären in welcher Form das partielle Trisomie-8-Mosaik an der Leukämieentstehung beteiligt ist und in welcher Weise dies für verschiedenen Mutationssubtypen der JMML eine Rolle spielt.

Abstract

Juvenile myelomonocytic leukemia (JMML) is a unique myeloproliferative disorder of early childhood in which mutations in NRAS, KRAS, PTPN11, NF1 and CBL are frequently found. Using high-resolution oligo array-based comparative genomic hybridization (aCGH), 20 JMML samples were investigated for submicroscopic genomic copy number alterations. Besides known cytogenetic aberrations, ten samples displayed additional submicroscopic alterations. Interestingly, an almost identical gain of chromosome 8 was identified in two patients. Subsequently, fluorescence in situ hybridization indicated a constitutional partial trisomy 8 mosaic (cT8M) in both patients. A survey on 27 cT8M patients with reported malignancies showed a predominance of myeloid malignancies including JMML. Our results dramatically reduce the critical region on chromosome 8 to 8p11.21q11.21. To determine how constitutional partial trisomy 8 mosaicisms may contribute to leukemogenesis in different mutational subtypes of JMML and other myeloid malignancies, further investigations are required.

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Literatur

  1. 1.

    Akasaka T, Balasas T, Russell LJ et al (2007) Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood 109:3451–3461

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Ando S, Maemori M, Sakai H et al (2005) Constitutional trisomy 8 mosaicism with myelodysplastic syndrome complicated by intestinal Behcet disease and antithrombin III deficiency. Cancer Genet Cytogenet 162:172–175

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Basseres DS, Baldwin AS (2006) Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene 25:6817–6830

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Bernasconi P, Orlandi E, Cavigliano P et al (2000) Translocation (8;16) in a patient with acute myelomonocytic leukemia, occurring after treatment with fludarabine for a low-grade non-Hodgkin’s lymphoma. Haematologica 85:1087–1091

    PubMed  CAS  Google Scholar 

  5. 5.

    Borrow J, Stanton VP Jr, Andresen JM et al (1996) The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet 14:33–41

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Brady AF, Waters CS, Pocha MJ, Brueton LA (2000) Chronic myelomonocytic leukaemia in a child with constitutional partial trisomy 8 mosaicism. Clin Genet 58:142–146

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Bullinger L, Dohner K, Bair E et al (2004) Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 350:1605–1616

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Cappellini A, Tabellini G, Zweyer M et al (2003) The phosphoinositide 3-kinase/Akt pathway regulates cell cycle progression of HL60 human leukemia cells through cytoplasmic relocalization of the cyclin-dependent kinase inhibitor p27(Kip1) and control of cyclin D1 expression. Leukemia 17:2157–2167

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Champagne N, Pelletier N, Yang XJ (2001) The monocytic leukemia zinc finger protein MOZ is a histone acetyltransferase. Oncogene 20:404–409

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Chen ZJ, Fuchs SY (2004) Ubiquitin-dependent activation of NF-kappaB: K63-linked ubiquitin chains: a link to cancer? Cancer Biol Ther 3:286–288

    PubMed  Article  Google Scholar 

  11. 11.

    Cornaglia-Ferraris P, Ghio R, Barabino A et al (1981) Diminished in vitro colony forming capacity of bone marrow cells in a case of chromosome 8 trisomy (mosaicism): criteria for „high risk“ pre-leukemia syndrome. Boll Ist Sieroter Milan 60:69–73

    PubMed  CAS  Google Scholar 

  12. 12.

    Fine LA, Hoffman LD, Hoffman MD (2007) Aphthous ulcerations associated with trisomy 8-positive myelodysplastic syndrome. J Am Acad Dermatol 57:38–41

    Article  Google Scholar 

  13. 13.

    Flotho C, Valcamonica S, Mach-Pascual S et al (1999) RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13:32–37

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Gafter U, Shabtal F, Kahn Y et al (1976) Aplastic anemia followed by leukemia in congenital trisomy 8 mosaicism. Ultrastructural studies of polymorphonuclear cells in peripheral blood. Clin Genet 9:134–142

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Ganmore I, Smooha G, Izraeli S (2009) Constitutional aneuploidy and cancer predisposition. Hum Mol Genet 18:R84–R93

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Guzman ML, Neering SJ, Upchurch D et al (2001) Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98:2301–2307

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Haferlach T, Kohlmann A, Klein HU et al (2009) AML with translocation t(8;16)(p11;p13) demonstrates unique cytomorphological, cytogenetic, molecular and prognostic features. Leukemia 23:934–943

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Hasle H, Clausen N, Pedersen B, Bendix-Hansen K (1995) Myelodysplastic syndrome in a child with constitutional trisomy 8 mosaicism and normal phenotype. Cancer Genet Cytogenet 79:79–81

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Horwitz M (1997) The genetics of familial leukemia. Leukemia 11:1347–1359

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Iwai K, Tokunaga F (2009) Linear polyubiquitination: a new regulator of NF-kappaB activation. EMBO Rep 10:706–713

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Kapaun P, Kabisch H, Held KR et al (1993) Atypical chronic myelogenous leukemia in a patient with trisomy 8 mosaicism syndrome. Ann Hematol 66:57–58

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Karadima G, Bugge M, Nicolaidis P et al (1998) Origin of nondisjunction in trisomy 8 and trisomy 8 mosaicism. Eur J Hum Genet 6:432–438

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Knuutila S, Teerenhovi L, Larramendy ML et al (1994) Cell lineage involvement of recurrent chromosomal abnormalities in hematologic neoplasms. Genes Chromosomes Cancer 10:95–102

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Kratz CP, Niemeyer CM, Castleberry RP et al (2005) The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106:2183–2185

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Lauchle JO, Braun BS, Loh ML, Shannon K (2006) Inherited predispositions and hyperactive Ras in myeloid leukemogenesis. Pediatr Blood Cancer 46:579–585

    PubMed  Article  Google Scholar 

  26. 26.

    Lessick M, Israel J, Szego K, Wong P (1990) Leiomyosarcoma in a patient with trisomy 8 mosaicism. J Med Genet 27:643–644

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Loh ML, Sakai DS, Flotho C et al (2009) Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114:1859–1863

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Mark FL, Ahearn J, Lathrop JC (1995) Constitutional trisomy 8 mosaicism and gestational trophoblastic disease. Cancer Genet Cytogenet 80:150–154

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Marti S, Galan FM, Casero JM et al (2008) Characterization of trisomic natural killer cell abnormalities in a patient with constitutional trisomy 8 mosaicism. Pediatr Blood Cancer 25:135–146

    CAS  Google Scholar 

  30. 30.

    Maserati E, Aprili F, Vinante F et al (2002) Trisomy 8 in myelodysplasia and acute leukemia is constitutional in 15–20% of cases. Genes Chromosomes Cancer 33:93–97

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Maserati E, Pressato B, Valli R et al (2007) Constitutional trisomy 8 mosaicism in primary myelofibrosis: relevance to clinical practice and warning for trisomy 8 studies. Cancer Genet Cytogenet 179:79–81

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Mastrangelo R, Tornesello A, Mastrangelo S et al (1995) Constitutional trisomy 8 mosaicism evolving to primary myelodysplastic syndrome: a new subset of biologically related patients? Am J Hematol 48:67–68

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Nakamura Y, Nakashima H, Fukuda S et al (1985) Bilateral cystic nephroblastomas and multiple malformations with trisomy 8 mosaicism. Hum Pathol 16:754–756

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Narendran A, Hawkins LM, Ganjavi H et al (2004) Characterization of bone marrow stromal abnormalities in a patient with constitutional trisomy 8 mosaicism and myelodysplastic syndrome. Pediatr Hematol Oncol 21:209–221

    PubMed  Article  Google Scholar 

  35. 35.

    Nielsen J, Wohlert M (1991) Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet 87:81–83

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Niemeyer CM, Arico M, Basso G et al (1997) Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood 89:3534–3543

    PubMed  CAS  Google Scholar 

  37. 37.

    Niemeyer CM, Kang MW, Shin DH et al (2010) Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42:794–800

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Niss R, Passarge E (1976) Trisomy 8 restricted to cultured fibroblasts. J Med Genet 13:229–234

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Nylund SJ, Verbeek W, Larramendy ML et al (1993) Cell lineage involvement in four patients with myelodysplastic syndrome and t(1;7) or trisomy 8 studied by simultaneous immunophenotyping and fluorescence in situ hybridization. Cancer Genet Cytogenet 70:120–124

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Palmer CG, Provisor AJ, Weaver DD et al (1983) Juvenile chronic granulocytic leukemia in a patient with trisomy 8, neurofibromatosis, and prolonged Epstein-Barr virus infection. J Pediatr 102:888–892

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Paulsson K, Johansson B (2007) Trisomy 8 as the sole chromosomal aberration in acute myeloid leukemia and myelodysplastic syndromes. Pathol Biol (Paris) 55:37–48

    Google Scholar 

  42. 42.

    Paulsson K, Panagopoulos I, Knuutila S et al (2003) Formation of trisomies and their parental origin in hyperdiploid childhood acute lymphoblastic leukemia. Blood 102:3010–3015

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Riccardi VM, Humbert JR, Peakman D (1978) Acute leukemia associated with trisomy 8 mosaicism and a familial translocation 46, XY, t(7;20)(p13;p12). Am J Med Genet 2:15–21

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Ripperger T, Tauscher M, Praulich I et al (2011) Constitutional trisomy 8p11.21-q11.21 mosaicism: a germline alteration predisposing to myeloid leukaemia. Br J Haematol 155:209–217

    PubMed  Article  Google Scholar 

  45. 45.

    Schaich M, Schlenk RF, Al Ali HK et al (2007) Prognosis of acute myeloid leukemia patients up to 60 years of age exhibiting trisomy 8 within a non-complex karyotype: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup. Haematologica 92:763–770

    PubMed  Article  Google Scholar 

  46. 46.

    Seghezzi L, Maserati E, Minelli A et al (1996) Constitutional trisomy 8 as first mutation in multistep carcinogenesis: clinical, cytogenetic, and molecular data on three cases. Genes Chromosomes Cancer 17:94–101

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Steinemann D, Arning L, Praulich I et al (2010) Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1. Haematologica 95:320–323

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Stiller CA, Chessells JM, Fitchett M (1994) Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70:969–972

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Storlazzi CT, Fioretos T, Paulsson K et al (2004) Identification of a commonly amplified 4.3 Mb region with overexpression of C8FW, but not MYC in MYC-containing double minutes in myeloid malignancies. Hum Mol Genet 13:1479–1485

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Sun T, Wu E (2001) Acute monoblastic leukemia with t(8;16): a distinct clinicopathologic entity; report of a case and review of the literature. Am J Hematol 66:207–212

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Swarthout JT, Lobo S, Farh L et al (2005) DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras. J Biol Chem 280:31141–31148

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Tartaglia M, Gelb BD (2005) Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet 6:45–68

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Tartaglia M, Niemeyer CM, Fragale A et al (2003) Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34:148–150

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Virtaneva K, Wright FA, Tanner SM et al (2001) Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics. Proc Natl Acad Sci U S A 98:1124–1129

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Wang T, Danielson PD, Li BY et al (1996) The p21(RAS) farnesyltransferase alpha subunit in TGF-beta and activin signaling. Science 271:1120–1122

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Welborn J (2004) Constitutional chromosome aberrations as pathogenetic events in hematologic malignancies. Cancer Genet Cytogenet 149:137–153

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Wu X, Yamamoto M, Akira S, Sun SC (2009) Regulation of hematopoiesis by the K63-specific ubiquitin-conjugating enzyme Ubc13. Proc Natl Acad Sci U S A 106:20836–20841

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Yamamoto K, Okamura A, Kawano H et al (2007) A novel t(8;18)(q13;q21) in acute monocytic leukemia evolving from constitutional trisomy 8 mosaicism. Cancer Genet Cytogenet 176:144–149

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Zollino M, Genuardi M, Bajer J et al (1995) Constitutional trisomy 8 and myelodysplasia: report of a case and review of the literature. Leuk Res 19:733–736

    PubMed  Article  CAS  Google Scholar 

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Danksagung

Wir danken allen an der Studie beteiligten Patienten und Kollegen. Die Arbeit von Tim Ripperger wurde zum Teil durch ein Stipendium der Hannover Biomedical Research School, PhD Programm Molecular Medicine finanziert. Abschließend danken wir Gillian Teicke für die kritische Durchsicht des Manuskriptes und dem British Journal of Haematology (Wiley-Blackwell), dass wir die Abbildung aus der Originalpublikation des Artikels [44] weitestgehend identisch verwenden konnten.

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Ripperger, T., Schlegelberger, B. & Steinemann, D. Mosaiktrisomie 8p11.21q11.21 als Prädisposition für myeloische Leukämien. medgen 24, 33–39 (2012). https://doi.org/10.1007/s11825-012-0316-1

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Schlüsselwörter

  • Juvenile myelomonozytäre Leukämie
  • Arraybasierte komparative genomische Hybridisierung
  • Trisomie 8
  • Leukämieprädisposition

Keywords

  • Juvenile myelomonocytic leukemia
  • Array-based comparative genomic hybridization
  • Trisomy 8
  • Leukemic predisposition