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Pathogenetic insight and prognostic information from standard and molecular cytogenetic studies in the BCR-ABL-negative myeloproliferative neoplasms (MPNs)

Leukemia volume 22, pages 1818–1827 (2008)Cite this article

Abstract

The frequency of cytogenetic abnormalities in the Philadelphia-negative myeloproliferative neoplasms (MPNs) varies from approximately 30% in primary myelofibrosis (PMF) to less than 5% in essential thrombocytosis (ET). The spectrum of aberrations is heterogeneous, ranging from gains and losses of genetic material to structural changes including unbalanced translocations. However, no specific abnormality has been identified to date. Nevertheless, such investigations can provide evidence of clonality and, as a result, cytogenetic findings have been included in the WHO diagnostic criteria for this group of diseases. The aim of the current review is to discuss the pathogenetic insight and prognostic information that standard, as well as molecular cytogenetic analysis has provided. A brief overview is given of the cytogenetic findings in the individual diseases, followed by a more detailed discussion of the possible pathogenetic consequences of specific abnormalities and their impact on prognosis.

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References

  1. Tefferi A, Vardiman JW . Classification and diagnosis of myeloprolifertaive neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukaemia 2008; 22: 14–22.

    CAS  Google Scholar 

  2. Nowell PC, Hungerford DA . Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 1960; 25: 85–109.

    CAS  PubMed  Google Scholar 

  3. Rowley JD . A new and consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1972; 243: 290–293.

    Google Scholar 

  4. Bartram CR, de Klein A, Hagemeijer A, van Agthoven T, Geurts van Kessel A, Bootsma D et al. Translocation of c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1983; 306: 277–280.

    CAS  PubMed  Google Scholar 

  5. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the bcr-abl tyrosine kinase in chronic myeloid leukaemia. N Engl J Med 2001; 344: 1031–1037.

    CAS  PubMed  Google Scholar 

  6. Golub TR, Barker GF, Lovett M, Gilliland DG . Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77: 307–316.

    CAS  PubMed  Google Scholar 

  7. Ross TS, Bernard OA, Berger R, Gilliland DG . Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor α receptor (PDGFαR) in chronic myelomonocytic leukaemia with t(5;7)(q33;q11.2). Blood 1998; 91: 4419–4426.

    CAS  PubMed  Google Scholar 

  8. Cools J, De Angelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J et al. A tyrosine kinase created by fusion of the PDGFRA and FLIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Eng J Med 2003; 348: 1201–1214.

    CAS  Google Scholar 

  9. Bain BJ . An overview of translocation-related oncogenesis in the chronic myeloid leukaemias. Acta Haematologica 2002; 107: 57–63.

    CAS  PubMed  Google Scholar 

  10. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.

    Article  CAS  PubMed  Google Scholar 

  11. James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 28: 1144–1148.

    Google Scholar 

  12. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Eng J Med 2005; 352: 1779–1790.

    CAS  Google Scholar 

  13. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–397.

    Article  CAS  PubMed  Google Scholar 

  14. Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005; 280: 22788–22792.

    CAS  PubMed  Google Scholar 

  15. Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis from an ad hoc international expert panel. Blood 2007; 110: 1092–1097.

    Article  CAS  PubMed  Google Scholar 

  16. Spivak JL, Silver RT . The revised World Health Organization criteria for polycythemia vera, essential thrombocytosis and primary myelofibrosis: an alternative proposal. Blood 2008; 112: 231–239.

    CAS  PubMed  Google Scholar 

  17. Reilly JT . Pathogenesis and management of idiopathic myelofibrosis. Bailliere's Clin Haematol 1998; 11: 751–767.

    CAS  Google Scholar 

  18. Greenberg BR, Woo L, Veomett IC, Payne CM, Ahmann FR . Cytogenetics of bone marrow fibroblastic cells in idiopathic chronic myelofibrosis. Brit J Haem 1987; 66: 487–490.

    CAS  Google Scholar 

  19. Wang JC, Lang HD, Lichter S, Weinstein M, Benn P . Cytogenetic studies of bone marrow fibroblasts cultured from patients with myelofibrosis and myeloid metaplasia. Brit J Haem 1992; 80: 184–188.

    CAS  Google Scholar 

  20. Greenberg BR, Wilson FD, Woo L, Jenks HM . Cytogenetics of fibroblastic colonies in Ph1-positive chronic myelogenous leukemia. Blood 1978; 51: 1039–1044.

    CAS  PubMed  Google Scholar 

  21. Forrester RH, Louro JM . Philadelphia chromosome abnormality in agnogenic myeloid metaplasia. Ann Intern Med 1966; 64: 622–627.

    CAS  PubMed  Google Scholar 

  22. Chen F, Zhang C, Wang W, Li L, Yan S, Sun J et al. A case of Philadelphia-chromsome positive chronic idiopathic myelofibrosis. Leuk Res 2007; 32: 665–667.

    PubMed  Google Scholar 

  23. Reilly JT, Wilson G, Barnett D, Watmore A, Potter A . Karyotypic and ras gene mutational analysis in idiopathic myelofibrosis. Br J Haematol 1994; 88: 575–581.

    CAS  PubMed  Google Scholar 

  24. Okamura T, Kinukawa N, Niho Y, Mizoguchi H . Primary chronic myelofibrosis: clinical and prognostic evaluation in 336 Japanese patients. Int J Haematol 2001; 73: 194–198.

    CAS  Google Scholar 

  25. Tefferi A . Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol 2005; 23: 8520–8530.

    CAS  PubMed  Google Scholar 

  26. Demory JL, Dupriez B, Fenaux P, Laï JL, Beuscart R, Jouet JP et al. Cytogenetic studies and their prognostic significance in agnogenic myeloid metaplasia: a report on 47 cases. Blood 1988; 72: 855–859.

    CAS  PubMed  Google Scholar 

  27. Reilly JT, Snowden JA, Spearing RL, Fitzgerald PM, Jones N, Watmore A et al. Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases. Brit J Haematol 1997; 98: 96–102.

    CAS  Google Scholar 

  28. Tefferi A, Mesa RA, Schroeder G, Hanson CA, Li CY, Dewald GW . Cytogenetic findings and their clinical relevance in myelofibrosis with myeloid metaplasia. Br J Haematol 2001; 113: 763–771.

    CAS  PubMed  Google Scholar 

  29. Bench AJ, Nacheva EP, Champion KM, Green AR . Molecular genetics and cytogenetics of myeloproliferative disorders. Bailliere's Clin Haematol 1998; 11: 819–848.

    CAS  Google Scholar 

  30. Börgstrom GH, Knuutila S, Ruutu T, Pakkala A, Lahtinen R, de la Chapelle A . Abnormalities of chromosome 13 in myelofibrosis. Scand J Haematol 1984; 33: 15–21.

    PubMed  Google Scholar 

  31. Dingli D, Grand FH, Mahaffey V, Spurbeck J, Ross FM, Watmore AE et al. Der(6)t(1;6)(q21–23;p21.3): the first specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia. Br J Haematol 2005; 130: 229–232.

    CAS  PubMed  Google Scholar 

  32. Giraudier S, Chagraoui H, Komura E, Barnache S, Blanchet B, LeCouedic JP et al. Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors. Blood 2002; 100: 2932–2940.

    CAS  PubMed  Google Scholar 

  33. Tokita K, Maki K, Tadokoro J, Nakamura Y, Arai Y, Sasaki K et al. Chronic idiopathic myelofibrosis expressing a novel type of TEL-PDGFRB chimaera responded to imatinib mesylate therapy. Leukamia 2007; 21: 190–192.

    CAS  Google Scholar 

  34. Jones LC, Tefferi A, Vuong PT, Desmond JC, Hofmann WK, Koeffler HP . Detection of aberrant gene expression in CD34+ hematopoietic stem cells from patients with agnogenic myeloid metaplasia using oligonucleotide microarrays. Stem Cells 2005; 23: 631–637.

    CAS  PubMed  Google Scholar 

  35. Guglielmelli P, Zini R, Bogani C, Salati S, Pancrazzi A, Bianchi E et al. Molecular profiling of CD34+ cells in idiopathic myelofibrosis identifies a set of disease-associated genes and reveals the clinical significance of Wilms' tumor gene 1 (WT1). Stem Cells 2007; 25: 165–173.

    CAS  PubMed  Google Scholar 

  36. Jones LC, Tefferi A, Idos GE, Kumagai T, Hofmann WK, Koeffler HP . RARbeta2 is a candidate tumor suppressor gene in myelofibrosis with myeloid metaplasia. Oncogene 2004; 23: 7846–7853.

    Article  CAS  PubMed  Google Scholar 

  37. Anonymous. Report on essential thrombocythemia. Cancer Genet Cytogenet 1981; 4: 138–142.

    Google Scholar 

  38. Sessarego M, Defferrari R, Dejana AM, Rebuttato AM, Fugazza G, Salvidio E et al. Cytogenetic analysis in essential thrombocythemia at diagnosis and at transformation. A 12-year study. Cancer Genet Cytogenet 1989; 43: 57–65.

    CAS  PubMed  Google Scholar 

  39. Bacher U, Haferlach T, Kern W, Hiddemann W, Schnittger S, Schoch C . Conventional cytogenetics of myeloproliferative disease other than CML contribute valid information. Ann Haematol 2005; 84: 250–257.

    Google Scholar 

  40. Case DC . Absence of a specific chromosomal marker in essential thrombocythemia. Cancer Genet Cytogenet 1984; 12: 163–165.

    PubMed  Google Scholar 

  41. Zamora L, Espinet B, Florensa L, Besses C, Salido M, Solé F . Incidence of trisomy 8 and 9, deletion of D13S319 and D20S108 loci and BCR/ABL translocation in non-treated essential thrombocythemia patients: an analysis of bone marrow cells using interphase fluorescence in situ hybridization. Haematologica 2003; 88: 110–111.

    CAS  PubMed  Google Scholar 

  42. Elis A, Amiel A, Manor Y, Tangi I, Fejgin M, Lishner M . The detection of trisomies 8 and 9 in patients with essential thrombocythosis by fluorescence in situ hybridization. Cancer Genet Cytogenet 1996; 92: 14–17.

    CAS  PubMed  Google Scholar 

  43. Swolin B, Safai-Kutti S, Angham E, Kutti J . No increased frequency of trisomies 8 and 9 by fluorescence in situ hydridization in untreated patients with essential thrombocythemia. Cancer Genet Cytogenet 2001; 126: 56–59.

    CAS  PubMed  Google Scholar 

  44. Hussein K, Ketterling RP, Dewald GW, Van Dyke DL, Mesa R, Hanson CA et al. Peripheral blood cytogenetic studies in myelofibrosis: overall yield and comparison with bone marrow cytogenetic studies. Leukaemia 2008; 32: 1597–1600.

    CAS  Google Scholar 

  45. Tefferi A, Meyer RG, Wyatt WA, Dewald GW . Comparison of peripheral blood interphase cytogenetics with bone marrow karyotype analysis in myelofibrosis with myeloid metaplasia. Br J Haematol 2001; 115: 316–319.

    CAS  PubMed  Google Scholar 

  46. Steensma DP, Tefferi A . Cytogenetic and molecular genetic aspects of essential thrombocthemia. Acta Haematol 2003; 108: 55–65.

    Google Scholar 

  47. Mesa RA, Li C-Y, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A . Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood 2005; 105: 973–977.

    CAS  PubMed  Google Scholar 

  48. Michiels JJ, Berneman Z, Schroyens W, Kutti J, Swolin B, Ridell B et al. Philadelphia (Ph) chromosome-positive thrombocythemia without features of chronic myeloid leukaemia in peripheral blood: natural history and diagnostic differentiation from Ph-negative essential thrombocythemia. Ann Hematol 2004; 83: 504–512.

    PubMed  Google Scholar 

  49. Mishra P, Mahapatra M, Kumar R, Dixit A, Chatterjee T, Tyagi S et al. Philadelphia-chromosome positive thrombocythemia in a child. Eur J Haematol 2005; 75: 262–263.

    PubMed  Google Scholar 

  50. Rice L, Popat U . Every case of essential thrombocythemia should be tested for the Philadelphia chromosome. Am J Hematol 2005; 78: 71–73.

    PubMed  Google Scholar 

  51. Kantarjian HM, Talpaz M, O'Brien S, Jones D, Giles F, Garcia-Manero G et al. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 2006; 108: 1835–1840.

    CAS  PubMed  Google Scholar 

  52. Knuutila S, Ruutu T, Partanen S, Vuopio P . Chromosome 1q+ in erythroid and granulocyte-monocyte precursors in a patient with essential thrombocythemia. Cancer Genet Cytogenet 1983; 9: 245–249.

    CAS  PubMed  Google Scholar 

  53. Swolin B, Weinfeld A, Westin J . A prospective long-term cytogenetic study in polycythemia vera in relation to treatment and clinical course. Blood 1988; 72: 386–395.

    CAS  PubMed  Google Scholar 

  54. Diez-Martin JL, Graham DL, Petitt RM, Dewald GW . Chromosome studies in 104 patients with polycythemia vera. Mayo Clin Proc 1991; 66: 287–299.

    CAS  PubMed  Google Scholar 

  55. Rege-Cambrin G, Mecucci C, Tricot G, Michaux JL, Louwagie A, Van Hove W et al. A chromosomal profile of polycythemia vera. Cancer Genet Cytogenet 1987; 25: 233–245.

    CAS  PubMed  Google Scholar 

  56. Testa JR, Kanofsky JR, Rowley JD, Baron JM, Vardiman JW . Karyotypic patterns and their clinical significance in polycythemia vera. Am J Hematol 1981; 11: 29–45.

    CAS  PubMed  Google Scholar 

  57. Dewald GW, Wright PI . Chromosome abnormalities in the myeloproliferative disorders. Semin Oncol 1995; 22: 341–354.

    CAS  PubMed  Google Scholar 

  58. Gangat N, Strand J, Lasho TL, Finke CM, Knudson RA, Pardanani A et al. Cytogenetic studies at diagnosis in polycythemia vera: clinical and JAK2 V617F allele burden correlates. Eur J Haematol 2008; 80: 197–200.

    PubMed  Google Scholar 

  59. Zamora L, Espinet B, Florensa L, Besses C, Woessner S, Serrano S et al. Is fluorescence in situ hydrodization a useful method in diagnosis of polycythemia vera patients. Cancer Genet Cytogenet 2004; 151: 139–145.

    CAS  PubMed  Google Scholar 

  60. Daibata M, Taguchi T, Taguchi H . A novel t(16;20)(q22;p13) in polycythemia vera. Cancer Genet Cytogenet 2002; 137: 29–32.

    CAS  PubMed  Google Scholar 

  61. Jaffe ES, Harris NL, Stein H, Vardiman JWE . World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. IARC: Lyon, 2001.

    Google Scholar 

  62. Reilly JT . Chronic neutrophilic leukaemia: a distinct clinical entity? Br J Haematol 2002; 116: 10–18.

    PubMed  Google Scholar 

  63. Verstovsek S, Lin H, Kantarjian H, Saglio G, De Micheli D, Pane F et al. Neutrophilic-chronic myeloid leukaemia: low levels of p230 BCR/ABL mRNA and undetectable BCR/ABL protein may predict an indolent course. Cancer 2002; 94: 2416–2425.

    CAS  PubMed  Google Scholar 

  64. Elliott MA . Chronic neutrophilic leukaemia and chronic myelomonocytic leukaemia: WHO defined. Best Pract Res Clin Haematol 2006; 19: 571–593.

    PubMed  Google Scholar 

  65. Orazi A, Cattoretti G, Sozzi G . A case of chronic neutrophilic leukemia with trisomy 8. Acta Hematologica 1989; 81: 148–151.

    CAS  Google Scholar 

  66. Hasle H, Olesen G, Kerndrup G, Philip P, Jacobsen N . Chronic neutrophilic leukaemia in adolescence and young adulthood. Br J Haematol 1996; 94: 628–630.

    CAS  PubMed  Google Scholar 

  67. Mehrotra PK, Winfield DA, Fergusson LH . Cellular abnormalities and reduced colony-forming cells in chronic neutrophilic leukemia. Acta Haematologica 1985; 73: 47–50.

    CAS  PubMed  Google Scholar 

  68. Yanagisawa K, Sato M, Takada K, Hasegawa H, Yasukawa M, Fujita S . Neoplastic involvement of granulocytic lineage, not granulocytic-monocytic, monocytic, or erythrocytic lineage, in a patient with chronic neutrophilic leukemia. Am J Hematol 1998; 57: 221–224.

    CAS  PubMed  Google Scholar 

  69. Bölm J, Kock S, Schaefer HE, Fisch P . Evidence of clonality in chronic neutrophilic leukemia. J Clin Path 2003; 56: 292–295.

    Google Scholar 

  70. Swolin B, Weinfeld A, Westin J . Trisomy 1q in polycythemia vera and its relation to disease transition. Am J Hematol 1986; 22: 155–167.

    CAS  PubMed  Google Scholar 

  71. Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F et al. Karyotypic abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet 2003; 140: 118–123.

    CAS  PubMed  Google Scholar 

  72. Gahrton G, Friburg K, Lindsten J, Zech L . Duplication of part of the long arm of chromosome 1 in myelofibrosis terminating in acute myeloblastic leukemia. Hereditas 1978; 88: 1–5.

    CAS  PubMed  Google Scholar 

  73. Donti E, Tabilio A, Bocchini F, Falzetti F, Martelli MF, Grignani F et al. Partial trisomy 1q in idiopathic myelofibrosis. Leuk Res 1990; 14: 1035–1040.

    CAS  PubMed  Google Scholar 

  74. Sawyer JR, Tricot G, Mattox S, Jagannath S, Barlogie B . Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentomeric heterochromatin. Blood 1998; 91: 1732–1741.

    CAS  PubMed  Google Scholar 

  75. Michaux L, Dierlamm J, Mecucci C, Meeus P, Ameye G, Libouton JM et al. Dicentric (1;15) in myeloid disorders. Cancer Genet Cytogenet 1996; 88: 86–89.

    CAS  PubMed  Google Scholar 

  76. Sambani C, La Starza R, Pierini V, Vandenberghe P, Gonzales-Aguilera JJ, Rigana H et al. Leukemic recombinations involving heterochromatin in myeloproliferative disorders with t(1;9). Cancer Genet Cytogenet 2005; 162: 45–49.

    CAS  PubMed  Google Scholar 

  77. Zanke B, Squire J, Griesser H, Henry M, Suzuki H, Patterson B et al. A hematopoietic protein tyrosine phosphatase (hePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1. Leukemia 1994; 8: 236–244.

    CAS  PubMed  Google Scholar 

  78. Busson-Le Coniat M, Salomon-Nguven F, Dastugue N, Maarek O, Lafage-Pochitaloff M, Mozziconacci M-J et al. Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in hematopoietic disorders: rearrangements of DNA satellite II and new recurrent translocations. Leukemia 1999; 13: 1975–1981.

    CAS  PubMed  Google Scholar 

  79. ISCN. An international system for human cytogenetic nomenclature (1985) ISCN. Report of the Standing Committee on Human Cytogenetic Nomenclature. Birth Defects Org Artic Ser 1985; 21: 1–117.

    Google Scholar 

  80. Jenkins RB, Le Beau MM, Kraker WJ, Borell TJ, Stalboerger PG, Davis EM et al. Fluorescence in situ hydridization: a sensitive method for trisomy 8 detection in bone marrow specimens. Blood 1992; 79: 3307–3315.

    CAS  PubMed  Google Scholar 

  81. Garzon R, Volinia S, Liu C-G, Fernandez-Cymering C, Palumbo T, Pichiorri F et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 2008; 111: 3183–3189.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Chen CZ, Li L, Lodish H, Bartel D . MicroRNAs modulate hematopoietic lineage differentiation. Science 2004; 303: 83–86.

    CAS  PubMed  Google Scholar 

  83. Lim LP, Lau LC, Garrett-Engele P, Grimson A, Schelter JM, Castle J et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433: 769–773.

    CAS  PubMed  Google Scholar 

  84. Amiel A, Gaber E, Manor Y, Fejgin M, Joseph-Lerner N, Ravid M et al. Fluorescence in situ hybridization for the detection of trisomies 8 and 9 in polycythemia vera. Cancer Genetic Cytogenet 1995; 79: 153–156.

    CAS  Google Scholar 

  85. Blij-Philipsen MVD, Stelink F, Vlasveld LTh . Partial trisomy 9 in a patient with polycythaemia vera. Cancer Genetic Cytogenet 1997; 97: 81–82.

    CAS  Google Scholar 

  86. Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K et al. Gain of 9p in the pathogenesis of polycythemia vera. Genes Chromosomes Cancer 1998; 22: 321–324.

    CAS  PubMed  Google Scholar 

  87. Westwood NB, Gruszka-Westwood AM, Pearson CE, Delford CF, Green AR, Huntly BJ et al. The incidence of trisomy 8, trisomy 9 and D20S108 deletion in polycythaemia vera: an analysis of blood granulocytes using interphase fluorescence in situ hybridization. Br J Haematol 2000; 110: 839–846.

    CAS  PubMed  Google Scholar 

  88. Westwood NB, Gruszka-Westwood AM, Atkinson S, Pearson TC . Polycythemia vera: analysis of DNA from blood granulocytes using comparative genomic hybridization. Hematologica 2001; 86: 464–469.

    CAS  Google Scholar 

  89. Van de Loosdrecht AA, deWolf J, Th M, Noordhoek L, van den Berg E . Partial trisomy of 9p: a rare chromosomal abnormality in polycythaemia vera. Br J Haematol 2001; 112: 1086–1087.

    CAS  PubMed  Google Scholar 

  90. Bacher U, Haferlach T, Schoche C . Gain of 9p to an unbalanced rearrangement der (9;18): a recurrent clonal abnormality in chronic myeloproliferative disorders. Cancer genet Cytogenet 2005; 160: 179–183.

    CAS  PubMed  Google Scholar 

  91. Al-Assar O, Ul-Hassan A, Brown A, Wilson GA, Hammond DW, Reilly JT . Gains of 9p are common genomic aberrations in idiopathic myelofibrosis: a comparative genomic hydridization study. Br J Haematol 2005; 129: 66–71.

    CAS  PubMed  Google Scholar 

  92. Helias C, Struski S, Gervais C, Leymarie V, Mauvieux L, Herbrecht R et al. Polycythaemia vera transforming to acute myeloid leukemia and complex abnormalities of MLLT3, JMJD2C, JAK2, and SMARCA2. Cancer Genetic Cytogenetic 2008; 180: 51–55.

    CAS  Google Scholar 

  93. Najfeld V, Montella L, Scalise A, Fruchtman S . Exploring polycythaemia vera with fluorescence in situ hybridiztion: additional cryptic 9p is the most frequent abnormality detected. Br J Haematol 2002; 119: 558–566.

    PubMed  Google Scholar 

  94. Kralovics R, Guan Y, Prchal JT . Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia. Exp Hematol 2002; 30: 229–236.

    CAS  PubMed  Google Scholar 

  95. Kvalovics R, Stockton DW, Prchal JT . Clonal haematopoiesis in familial polycythemia vera suggests involvement of multiple mutational events in the early pathogenesis of the disease. Blood 2003; 102: 3793–3796.

    Google Scholar 

  96. Morris CM, Cochrane JM, Benjes SM, Crossen PE, Fitzgerald PH . Molecular definition of interstitial deletions of chromosome 13 in leukaemia cells. Genes Chromosomes Cancer 1991; 3: 455–460.

    CAS  PubMed  Google Scholar 

  97. Lebowitz P, Papac R, Ghosh PK . Impaired retinoblastoma susceptibility (Rb) gene expression in agnogenic myeloid metaplasia. Blood 1990; 76 (Suppl): 236a.

    Google Scholar 

  98. Pastore C, Nomdedeu J, Volpe G, Guerrasio A, Cambrin GR, Parvis G et al. Genetic analysis of chromosome 13 deletions in bcr-abl negative chronic myeloproliferative disorders. Genes Chromosomes Cancer 1995; 14: 106–111.

    CAS  PubMed  Google Scholar 

  99. Juneau AL, Kaehler M, Christensen ER, Schad CR, Zinsmeister AR, Lust J et al. Detection of RB1 deletions by fluorescence in situ hybridizationin malignant hematologic disorders. Cancer Genet Cytogenet 1998; 103: 117–123.

    CAS  PubMed  Google Scholar 

  100. Tanaka K, Arif M, Eguchi M, Guo SX, Hayashi Y, Asaoku H et al. Frequenct allelic loss of the RB, D13S319 and D13S25 locus in myeloid malignaices with deletion/translocation at 13q14 of chromosome 13, but not in lymphoid malignancies. Leukemia 1999; 13: 1367–1373.

    CAS  PubMed  Google Scholar 

  101. La Starza R, Wlodarska I, Aventin A, Falzetti B, Crescenzi B, Martelli MF et al. Molecular delineation of 13q deletion boundaries in 20 patients with myeloid malignancies. Blood 1998; 91: 231–237.

    CAS  PubMed  Google Scholar 

  102. Sinclair EJ, Forrest EC, Reilly JT, Watemore AE, Potter AM . Fluorescence in situ hybridization analysis of 25 cases of idiopathic myelofibrosis and two cases of secondary myelofibrosis. Monoallelic loss of RB1, D13S319 and D13S25 loci associated with cytogenetic deletion and translocation involving 13q14. Br J Haematol 2001; 113: 365–368.

    CAS  PubMed  Google Scholar 

  103. Asimakopoulos FA, Gilbert JG, Aldred MA, Pearson TC, Green AR . Interstitial deletion constitutes the major mechanism for loss of heterozygosity on chromosome 20q in polycythemia vera. Blood 1996; 88: 2690–2698.

    CAS  PubMed  Google Scholar 

  104. Gardiner AC, Corcoran MM, Oscier DG . Cytogenetic, fluorescent in situ hybridization and clinical of translocations with concomitant deletion of 13q14 in chronic lymphatic leukemia. Genes Chromosomescancer 1997; 20: 73–81.

    CAS  Google Scholar 

  105. Hawthorn LA, Chapman R, Oscier D, Cowell JK . The consistent 13q14 translocation breakpoint in chronic B-cell leukemia (BCLL) involves deletion of the D13S25 locus, which lies distal to the retinoblastoma predisposition gene. Oncogene 1993; 8: 1415–1419.

    CAS  PubMed  Google Scholar 

  106. Macdonald DHC, Lahiri D, Chase A, Sohal J, Goldman JM, Cross NCP . A case of myelofibrosis with a t(4;13)(q25;q12): evidence for involvement of a second 13q12 locus in chronic myeloproliferative disorders. Br J Haematol 1999; 105: 771–774.

    CAS  PubMed  Google Scholar 

  107. Mertens F, Sallerfors B, Heims S, Johansson B, Kristoffersson U, Malm C et al. Trisomy as a primary aberration in acute leukaemia. Cancer Genet Cytogenet 1991; 56: 39–44.

    CAS  PubMed  Google Scholar 

  108. Djordjevic V, Dencic-Fekete M, Javanovic J, Bizics S, Jankovic G, Bogdanovic A et al. Cytogenetics of agnogenic myeloid metaplasia: a study of 61 patients. Cancer Genet Cytogenet 2007; 173: 57–62.

    CAS  PubMed  Google Scholar 

  109. Cabrol C, Samii K, Scherrer A, Darbellay R, Beris P . Trisomy 13 in a Philadelphia negative chromosome and bcr-abl negative myeloproliferative disorder. Cancer Genet Cytogenet 1999; 111: 184–185.

    CAS  PubMed  Google Scholar 

  110. Kay HE, Lawler SD, Millard RE . The chromosomes in polycythemia vera. Br J Haematol 1966; 12: 507–528.

    CAS  PubMed  Google Scholar 

  111. Aatola M, Armstrong E, Teerenhovi L, Borgstrom GH . Clinical significance of the del(20q) chromosome in hematologic disorders. Cancer Genet Cytogenet 1992; 62: 75–80.

    CAS  PubMed  Google Scholar 

  112. Mertens F, Johannsson B, Heim S, Kristofferssen U, Mitelman F . Karyotypic patterns in chronic myeloproliferative disorders: Report of 74 cases and review of the literature. Leukemia 1991; 5: 214–220.

    CAS  PubMed  Google Scholar 

  113. Nacheva E, Holloway T, Carter N, Grace C, White N, Green AR . Characterization of 20q deletions in patients with myeloproliferative disorders or myelodysplastic syndromes. Cancer Genet Cytogenet 1995; 80: 87–94.

    CAS  PubMed  Google Scholar 

  114. Fenaux P, Morel P, Lai JL . Cytogenetics of myelodysplastic syndromes. Semin Haematol 1996; 33: 127–138.

    CAS  Google Scholar 

  115. Heim S, Mitelman F . Cytogenetic analysis in the diagnosis of acute leukemia. Cancer 1992; 70: 1701–1709.

    CAS  PubMed  Google Scholar 

  116. Mitelman F . Catalog of Chromosome Aberrations in Cance. Wiley-Liss: New York, NY, 1991.

    Google Scholar 

  117. Kurtin PJ, Dewald GW, Shields DJ, Hanson CA . Hematologic disorders associated with deletion of chromosome 20q: a clinicopathologic study of 107 patients. Am J Clin Path 1996; 106: 680–688.

    CAS  PubMed  Google Scholar 

  118. Davis MP, Dewald GW, Pierre RV, Hoagland HC . Haematologic manifestations asscoaited with deletions of the long arm of chromosome 20. Cancer Genet Cytogenet 1984; 12: 63–71.

    CAS  PubMed  Google Scholar 

  119. Roulston D, Espinosa III R, Stoffel M, Bell GI, Le Beau MM . Molecular genetics of myeloid leukaemia: identification of the commonly deleted segment of chromosome 20. Blood 1993; 82: 3424–3429.

    CAS  PubMed  Google Scholar 

  120. Le Beau MM, Westbrook C, Diaz MO, Rowley JD . c-src is conistently conserved in the chromosomal deletion (20q) observed in myeloid disorders. Proc Natl Acad Sci USA 1985; 82: 6692–6696.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Morris CM, Honeybone LM, Hollings PE, Fitzgerald PH . Localization of the SRC oncogene to chromosome band 20q11.2 and loss of this gene with deletion (20q) in two leukemic patients. Blood 1989; 74: 1768–1773.

    CAS  PubMed  Google Scholar 

  122. Wang PW, Eisenbart JD, Espinosa R, Davis EM, Larson RA, Le Beau MM . Refinement of the smallest commonly deleted segment of chromosome 20 in malignant myeloid diseases and development of a PAC-based physical and transcription map. Genomics 2000; 67: 28–39.

    CAS  PubMed  Google Scholar 

  123. Bench AJ, Nacheva EP, Hood TL, Holden JL, French L, Swanton S et al. Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes. UK Cancer Cytogenetic Group (UKCCG). Oncogene 2000; 20: 4150–4160.

    Google Scholar 

  124. MacGrogan D, Alvarez S, DeBlasio T, Jhanwar SC, Nimer SD . Identification of candidate genes on chromosome band 20q12 by physical mapping of translocation breakpoints found in myeloid leukaemia cell lines. Oncogene 2001; 20: 4150–4160.

    CAS  PubMed  Google Scholar 

  125. Koga H, Matsui S, Hirota T, Takebayashi S, Okumura K, Saya H . A human homolog of Drosophila lethal (3) malignant brain tumor (1(3)mbt) protein associates with condensed mitotic chromosomes. Oncogene 1999; 18: 3799–3809.

    CAS  PubMed  Google Scholar 

  126. Boccuni P, MacGrogan D, Scandura JM, Nimer SD . The human L(3)MBT polycomb group protein is a transcriptional repressor and interacts physically and functionally with TEL (ETV6). J Bio Chem 2003; 278: 15412–15420.

    CAS  Google Scholar 

  127. Bench AJ, Li J, Huntly BJP, Delabesse E, Fourouclas N, Hunt AR et al. Characterization of the imprinted polycomb gene L3MBTL, a candidate 20q tumour suppressor gene, in patients with myeloid malignancies. Br J Haematol 2004; 127: 509–518.

    CAS  PubMed  Google Scholar 

  128. Li J, Bench AJ, Vassiliou GS, Fourouclas N, Ferguson-Smith AC, Green AC . Imprinting of the human L3MBTL gene, a polycomb family member located in a region of chromosome 20 deleted in human myeloid malignancies. Proc Natl Acad Sci USA 2004; 101: 7341–7346.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Knuutila S, Teerenhovi L, Larramendy ML, Elonen E, Franssila KO, Nylund SJ et al. Cell lineage involvement of recurrent chromosomal abnormalities in hematologic neoplasms. Genes, Chromsomes and Cancer 1994; 10: 95–102.

    CAS  Google Scholar 

  130. Hollings PE, Beard MEJ, Rosman I . A 20q deletion originating in a pluripotential stem cell. Blood 1994; 83: 306–307.

    Google Scholar 

  131. Morris CM, Honeybone LM, Hollings PE . Localization of the SRC oncogene to chromosome band 20q11.2 and loss of this gene with deletion (20q) in two leukemic patients. Blood 1989; 74: 1768–1773.

    CAS  PubMed  Google Scholar 

  132. Reeder TL, Bailey RJ, Dewald GW, Tefferi A . Both B and T lymphocytes may be clonally involved in myelofibrosis with myeloid metaplasia. Blood 2003; 101: 1981–1983.

    CAS  PubMed  Google Scholar 

  133. Buschle M, Janssen JWG, Drexler H, Lyons J, Anger B . Evidence for pluripotent stem cell origin of idiopathic myelofibrosis: clonal analysis of a case characterised by a N-ras mutation. Leukemia 1988; 2: 658–660.

    CAS  PubMed  Google Scholar 

  134. White NJ, Nacheva E, Asimakopoulos FA, Paul B, Green AR . Deletion of chromosome 20q in myelodysplasia can occur in a multipotent precursor of both myeloid cells and B cells. Blood 1994; 83: 2809–2816.

    CAS  PubMed  Google Scholar 

  135. Asimakopoulos FA, Holloway TL, Nacheva EP, Scott MA, Fenaux P, Green AR . Detection of chromosome 20q deletions in bone marrow metaphases but not peripheral blood granulocytes in patients with myeloproliferative disorders or myelodysplastic syndromes. Blood 1996; 87: 1561–1570.

    CAS  PubMed  Google Scholar 

  136. Campbell PJ, Baxter EJ, Beer PA, Scott LM, Bench AJ, Huntly BJ et al. Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood 2006; 108: 3548–3555.

    CAS  PubMed  Google Scholar 

  137. Najfeld V, Cozza A, Berkofsy-Fessler W, Prchal J, Scalise A . Numerical gain and structural rearrangements of JAK2, identified by FISH, characterize both JAK2617V>F-positive and -negative patients with Ph-negative MPD, myelodysplasia, and B-lymphoid neoplasms. Exp Hematol 2007; 35: 1668–1676.

    CAS  PubMed  Google Scholar 

  138. Delhommeau F, Pisani DF, Casadevall N, Constantinescu S, Vainchenker W . Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci 2006; 63: 2939–2953.

    CAS  PubMed  Google Scholar 

  139. Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 2007; 110: 375–379.

    CAS  PubMed  Google Scholar 

  140. Hsiao HH, Yang WC, Liu YC, Lee CP, Lin SF . Disappearance of JAK2 V617F mutation in a rapid leukemic transformed essential thrombocythemia patient. Leuk Res 2008; 32: 1323–1324.

    CAS  PubMed  Google Scholar 

  141. Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Tichelli A et al. Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 2006; 108: 1377–1380.

    CAS  PubMed  Google Scholar 

  142. Larsen TS, Hasselbalch HC, Pallisgaard N, Kerndrup GB . A der(18)t(9;18)(p13;p11) and a der(9;18)(p10;q10) in polycythemia vera associated with a hyperproliferative phenotype in transformation to postpolycythemia myelofibrosis. Cancer Genet Cytogenet 2007; 172: 107–112.

    CAS  PubMed  Google Scholar 

  143. Hsiao H-H, Ito Y, Sashida G, Ohyashiki JH, Ohyashiki K . De novo appearance of der(1;7)(q10;p10) is associated with leukemic transformation and unfavourable prognosis in essential thrombocythemia. Leuk Res 2005; 29: 1247–1252.

    CAS  PubMed  Google Scholar 

  144. Bernasconi P, Boni M, Cavigliano PM, Calatroni S, Brusamolino E, Passamonti F et al. Acute myeloid leukemia (AML) having evolved from essential thrombocythemia (ET): distinctive chromosome abnormalities in patients treated with pipobroman or hydroxyurea. Leukemia 2002; 16: 2078–2083.

    CAS  PubMed  Google Scholar 

  145. Willem P, Pinto M, Bernstein R . Translocation t(1;7) revisited. Report of three further cases and review. Cancer Genet Cytogenet 1998; 36: 45–54.

    Google Scholar 

  146. Hayashi S, Iwama H, Uchida Y, Kawakubo K, Inatomi Y, Nagasu M et al. Essential thrombocythemia in transformation to acute leukemia (FAB-M0) as a natural history from myelofibrosis with t(1;7). Jpn J Clin Hematol 1997; 38: 445–447.

    CAS  Google Scholar 

  147. Horsman DE, Kalousek DK . Acquired Robertsonian translocations in hematologic malignancy. A rare mechanism of clonal evolution. Cancer Genet Cytogenet 1990; 45: 193–196.

    CAS  PubMed  Google Scholar 

  148. Uesugi Y, Toba K, Nikkuni K, Fuse I, Koike T, Shibata A . Essential thrombocythemia in transformation to smouldering megakaryoblastic leukemia with myelofibrosis. Jpn J Clin Hematol 1995; 36: 1210–1216.

    CAS  Google Scholar 

  149. Rege-Cambrin G, Speleman F, Kerim S, Scaravaglio P, Carozzi F, Dal Cin P et al. Extra translocation +der(1q9p) is a poor indicator in myelofproliferative disorders. Leukemia 1991; 5: 1059–1063.

    CAS  PubMed  Google Scholar 

  150. Cox MC, Panetta P, Venditti A, Abruzzese E, Del Poeta G, Cantonette M et al. New reciprocal translocation t(6;10)(q27;q11) associated with idiopathic myelofibrosis. Leuk Res 2001; 25: 349–351.

    CAS  PubMed  Google Scholar 

  151. Andrieux J, Demory JL, Morel P, Plantier I, Dupriez B, Caulier MT et al. Frequency of structural abnormalities of the long arm of chromosome 12 in myelofibrosis with myeloid metaplasia. Cancer Genet Cytogenet 2002; 137: 68–71.

    CAS  PubMed  Google Scholar 

  152. Strasser-Weippl K, Steurer M, Kees M, Augustin F, Tzankov A, Dirnhofer S et al. Chromosome 7 deletions are associated with unfovourable prognosis in myelofibrosis with myeloid metaplasia. Blood 2005; 105: 4146.

    CAS  PubMed  Google Scholar 

  153. Patton WN, Bunce CM, Larkins S, Brown G . Defective erythropoiesis in primary myelofibrosis associated with chromosome 11 abnormalities. Br J Cancer 1991; 64: 128–131.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Besa EC, Nowell PC, Geller NL, Gardner FM . Analysis of the androgen response of 23 patients with agnogenic myeloid metaplasia. The value of chromosomal studies in predicting response and survival. Cancer 1982; 49: 308–313.

    CAS  PubMed  Google Scholar 

  155. Dupriez B, Morel P, Demory JL, Lai JL, Simon M, Plantier I et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 1996; 88: 1013–1018.

    CAS  PubMed  Google Scholar 

  156. Deeg HJ, Gooley TA, Flowers ME, Sale GE, Slattery JT, Anasetti C et al. Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 2003; 102: 3912–3918.

    CAS  PubMed  Google Scholar 

  157. Cervantes F, Barosi G, Demory J-L, Reilly J, Guarnone R, Dupriez B et al. Myelofibrosis with myeloid metaplasia in young individuals: disease characteristics, prognostic factors and identification of risk groups. Br J Haematol 1998; 102: 684–690.

    CAS  PubMed  Google Scholar 

  158. Cervantes F, Barosi G, Hernandez-Boluda J-C, Marchetti M, Montserrat E . Myelofibrosis with myeloid metaplasia in adult individuals 30 years old or younger: presenting features, evolution and survival. Eur J Haematol 2001; 66: 324–327.

    CAS  PubMed  Google Scholar 

  159. Altura RA, Head DR, Wang WC . Long-term survival of infants with idiopathic myelofibrosis. Br J Haematol 2000; 109: 459–462.

    CAS  PubMed  Google Scholar 

  160. Tefferi A, Dingli D, Li C-Y, Dewald GW . Prognostic diversity among cytogenetic abnormalities in myelofibrosis with myeloid metaplasia. Cancer 2005; 104: 1656–1660.

    CAS  PubMed  Google Scholar 

  161. Dingli D, Schwager SM, Mesa RA, Li C-Y, Dewald GW, Tefferi A . Presence of unfavourable cytogenetic abnormalities is the strongest predictor of poor survival in secondary myelofibrosis. Cancer 2006; 106: 1985–1989.

    PubMed  Google Scholar 

  162. Tefferi A, Lasho TL, Mesa RA, Pardanani A, Ketterling RP, Hanson CA . Lenalidomide therapy in del(5)(q31)-associated myelofibrosis: cytogenetic and KAK2V617F molecular remissions. Leukemia 2007; 21: 1827–1828.

    CAS  PubMed  Google Scholar 

  163. Tefferi A, Corthes J, Verstovsek S, Mesa RA, Thomas D, Lasho TL et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 2006; 108: 1158–1164.

    CAS  PubMed  Google Scholar 

  164. Verhelle D, Corral LG, Wong K, Mueller JH, Moutouch-de Parseval L, Jensen-Pergakes K et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res 2007; 15: 746–755.

    Google Scholar 

  165. Pellagatti A, Hellström-Linberg E, Giagounidis A, Perry J, Malcovati L, Della Porta MG et al. Haploinsufficiency of RPS14 in 5q- syndrome associated with deregulation of ribosomal- and translational-related genes. Br J Haematol 2008; 142: 57–64.

    CAS  PubMed  PubMed Central  Google Scholar 

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    J T Reilly

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Reilly, J. Pathogenetic insight and prognostic information from standard and molecular cytogenetic studies in the BCR-ABL-negative myeloproliferative neoplasms (MPNs). Leukemia 22, 1818–1827 (2008). https://doi.org/10.1038/leu.2008.218

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