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Table of Contents
Vol. 74, No. 2, 2007
Issue release date: June 2007
Section title: Review
Pathobiology 2007;74:72–80
(DOI:10.1159/000099120)

Histological and Molecular Classification of Chronic Myeloproliferative Disorders in the Age of JAK2: Persistence of Old Questions despite New Answers

Hussein K. · Bock O. · Kreipe H.
Institute of Pathology, Hannover Medical School, Hannover, Germany
email Corresponding Author

Abstract

The discovery of the Janus kinase 2 gain-of-function V617F mutation (JAK2V617F) provided a major breakthrough in the understanding of Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph CMPD). Among haematologic neoplasm the mutation appears to be almost specific for Ph CMPD but the different entities comprising polycythaemia vera (PV), essential thrombocythaemia and chronic idiopathic myelofibrosis (CIMF) are not discriminated by the mutation. It is unclear how the diversity with heterogeneous clinical and pathoanatomical presentations comes about. It has been suggested that differences in JAK2V617F gene dosage or different degrees to which the haematologic lineages are affected by the mutation could explain the heterogeneity of morphology and prognosis. Indeed the mutation mediates a PV-like phenotype but with regard to myelofibrosis JAK2V617F does not appear to be a causative factor. Megakaryocytes are homozygous in the majority of fibrotic CIMF and PV, whereas JAK2V617F heterozygosity is predominantly encountered in prefibrotic CIMF and essential thrombocythaemia but transition from hetero- to homozygosity with onset of fibrosis is rare. In conclusion, JAK2V617F provides a valuable adjunct to the diagnosis of Ph CMPD, in particular with regard to discrimination from reactive proliferations, but the challenge of correct subtyping and hence prognostication persists for clinicians and bone marrow pathologists.

© 2007 S. Karger AG, Basel


  

Key Words

  • Chronic myeloproliferative disorders
  • Classification
  • Janus kinase 2

References

  1. Jaffe SS, Harris NL, Sterm A, Vardiman JW: WHO Classification of Tumours: Tumours of Haematopoiesis and Lymphoid Tissues. Lyon, IARC, 2001, pp 31–42.
  2. Heuck G: Zwei Fälle von Leukämie mit eigentümlichem Blut resp. Knochenmarksbefund. Virchows Arch 1879;78:475.

    External Resources

  3. Dameshek W: Some speculations on the myeloproliferative syndromes. Blood 1951;6:372–375.
  4. Dameshek W: Physiopathology and course of polycythemia vera as related to therapy. J Am Med Assoc 1950;142:790–797.
  5. Berlin NI: Diagnosis and classification of the polycythemias. Semin Hematol 1975;12:339–351.
  6. Thiele J, Kvasnicka HM, Diehl V: Initial (latent) polycythemia vera with thrombocytosis mimicking essential thrombocythemia. Acta Haematol 2005;113:213–219.
  7. Kreft A, Büsche G, Ghalibafian M, Buhr T, Fischer T, Kirkpatrick CJ: The incidence of myelofibrosis in essential thrombocythaemia, polycythaemia vera and chronic idiopathic myelofibrosis: a retrospective evaluation of sequential bone marrow biopsies. Acta Haematol 2005;113:137–143.
  8. de Klein A, van Kessel AG, Grosveld G, Bartram CR, Hagemeijer A, Bootsma D, Spurr NK, Heisterkamp N, Groffen J, Stephenson JR: A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1982;300:765–767.
  9. Nowell PC, Hungerford DA: Chromosome studies on normal and leukemic leukocytes. J Natl Cancer Inst 1960;25:85–109.
  10. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–1148.
  11. Campbell PJ, Scott LM, Baxter EJ, Bench AJ, Green AR, Erber WN: Acquired mutation of the tyrosine kinase in human myeloproliferative disorders. Lancet 2005;365:1054–1061.
  12. Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, Zhao ZJ: Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280:22788–22792.
  13. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR; Cancer Genome Project: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054–1061.
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  19. Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG: Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 2006;107:4274–4281.
  20. Luo H, Rose P, Barber D, Hanratty WP, Lee S, Roberts TM, D’Andrea AD, Dearolf CR: Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and mammalian Jak-Stat pathways. Mol Cell Biol 1997;17:1562–1571.
  21. Cools J, Peeters P, Voet T, Aventin A, Mecucci C, Grandchamp B, Marynen P: Genomic organization of human JAK2 and mutation analysis of its JH2-domain in leukemia. Cytogenet Cell Genet 1999;85:260–266.
  22. Quentmeier H, MacLeod RA, Zaborski M, Drexler HG: JAK2 V617F tyrosine kinase mutation in cell lines derived from myeloproliferative disorders. Leukemia 2006;20:471–476.
  23. Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL, Gilliland DG, Tefferi A: The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both ‘atypical’ myeloproliferative disorders and myelodysplastic syndromes. Blood 2005;106:1207–1209.
  24. Mc Lornan DP, Percy MJ, Jones AV, Cross NC, Mc Mullin MF: Chronic neutrophilic leukemia with an associated V617F JAK2 tyrosine kinase mutation. Haematologica 2005;90:1696–1697.
  25. Lea NC, Lim Z, Westwood NB, Arno MJ, Gäken J, Mohamedali A, Mufti GJ: Presence of JAK2 V617F tyrosine kinase mutation as a myeloid-lineage-specific mutation in chronic neutrophilic leukaemia. Leukemia 2006;20:1324–1326.
  26. Ohyashiki K, Aota Y, Akahane D, Gotoh A, Miyazawa K, Kimura Y, Ohyashiki JH: The JAK2 V617F tyrosine kinase mutation in myelodysplastic syndromes (MDS) developing myelofibrosis indicates the myeloproliferative nature in a subset of MDS patients. Leukemia 2005;19:2359–2360.
  27. Johan MF, Goodeve AC, Bowen DT, Frew ME, Reilly JT: JAK2 V617F Mutation is uncommon in chronic myelomonocytic leukaemia. Br J Haematol 2005;130:968.
  28. Tono C, Xu G, Toki T, Takahashi Y, Sasaki S, Terui K, Ito E: JAK2 Val617Phe activating tyrosine kinase mutation in juvenile myelomonocytic leukemia. Leukemia 2005;19:1843–1844.
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  31. Bock O, Busche G, Koop C, Schroter S, Buhr T, Kreipe H: Detection of the single hotspot mutation in the JH2 pseudokinase domain of Janus kinase 2 in bone marrow trephine biopsies derived from chronic myeloproliferative disorders. J Mol Diagn 2006;8:170–177.
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  53. Bock O, Neuse J, Hussein K, Brakensiek K, Buesche G, Buhr T, Wiese B, Kreipe H: Aberrant collagenase expression in chronic idiopathic myelofibrosis is related to the stage of disease but not to the JAK2 mutation status. Am J Pathol 2006;169:471–481.
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Author Contacts

Prof. Hans Kreipe
Institute of Pathology, Medizinische Hochschule Hannover
Carl-Neuberg-Strasse 1
DE–30625 Hannover (Germany)
Tel. +49 511 532 4501, Fax +49 511 532 5799, E-Mail Kreipe.Hans@MH-Hannover.de

  

Article Information

Number of Print Pages : 9
Number of Figures : 0, Number of Tables : 1, Number of References : 58

  

Publication Details

Pathobiology

Vol. 74, No. 2, Year 2007 (Cover Date: June 2007)

Journal Editor: Yasui, W. (Hiroshima)
ISSN: 1015–2008 (print), 1423–0291 (Online)

For additional information: http://www.karger.com/PAT


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References

  1. Jaffe SS, Harris NL, Sterm A, Vardiman JW: WHO Classification of Tumours: Tumours of Haematopoiesis and Lymphoid Tissues. Lyon, IARC, 2001, pp 31–42.
  2. Heuck G: Zwei Fälle von Leukämie mit eigentümlichem Blut resp. Knochenmarksbefund. Virchows Arch 1879;78:475.

    External Resources

  3. Dameshek W: Some speculations on the myeloproliferative syndromes. Blood 1951;6:372–375.
  4. Dameshek W: Physiopathology and course of polycythemia vera as related to therapy. J Am Med Assoc 1950;142:790–797.
  5. Berlin NI: Diagnosis and classification of the polycythemias. Semin Hematol 1975;12:339–351.
  6. Thiele J, Kvasnicka HM, Diehl V: Initial (latent) polycythemia vera with thrombocytosis mimicking essential thrombocythemia. Acta Haematol 2005;113:213–219.
  7. Kreft A, Büsche G, Ghalibafian M, Buhr T, Fischer T, Kirkpatrick CJ: The incidence of myelofibrosis in essential thrombocythaemia, polycythaemia vera and chronic idiopathic myelofibrosis: a retrospective evaluation of sequential bone marrow biopsies. Acta Haematol 2005;113:137–143.
  8. de Klein A, van Kessel AG, Grosveld G, Bartram CR, Hagemeijer A, Bootsma D, Spurr NK, Heisterkamp N, Groffen J, Stephenson JR: A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1982;300:765–767.
  9. Nowell PC, Hungerford DA: Chromosome studies on normal and leukemic leukocytes. J Natl Cancer Inst 1960;25:85–109.
  10. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;434:1144–1148.
  11. Campbell PJ, Scott LM, Baxter EJ, Bench AJ, Green AR, Erber WN: Acquired mutation of the tyrosine kinase in human myeloproliferative disorders. Lancet 2005;365:1054–1061.
  12. Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, Zhao ZJ: Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280:22788–22792.
  13. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR; Cancer Genome Project: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054–1061.
  14. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779–1790.
  15. Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, Score J, Seear R, Chase AJ, Grand FH, White H, Zoi C, Loukopoulos D, Terpos E, Vervessou EC, Schultheis B, Emig M, Ernst T, Lengfelder E, Hehlmann R, Hochhaus A, Oscier D, Silver RT, Reiter A, Cross NC: Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106:2162–2168.
  16. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D’Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG: Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387–397.
  17. Jelinek J, Oki Y, Gharibyan V, Bueso-Ramos C, Prchal JT, Verstovsek S, Beran M, Estey E, Kantarjian HM, Issa JP: JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. Blood 2005;106:3370–3373.
  18. Lacout C, Pisani DF, Tulliez M, Moreau Gachelin F, Vainchenker W, Villeval JL: JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood 2006;108:1652–1660.
  19. Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG: Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 2006;107:4274–4281.
  20. Luo H, Rose P, Barber D, Hanratty WP, Lee S, Roberts TM, D’Andrea AD, Dearolf CR: Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and mammalian Jak-Stat pathways. Mol Cell Biol 1997;17:1562–1571.
  21. Cools J, Peeters P, Voet T, Aventin A, Mecucci C, Grandchamp B, Marynen P: Genomic organization of human JAK2 and mutation analysis of its JH2-domain in leukemia. Cytogenet Cell Genet 1999;85:260–266.
  22. Quentmeier H, MacLeod RA, Zaborski M, Drexler HG: JAK2 V617F tyrosine kinase mutation in cell lines derived from myeloproliferative disorders. Leukemia 2006;20:471–476.
  23. Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL, Gilliland DG, Tefferi A: The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both ‘atypical’ myeloproliferative disorders and myelodysplastic syndromes. Blood 2005;106:1207–1209.
  24. Mc Lornan DP, Percy MJ, Jones AV, Cross NC, Mc Mullin MF: Chronic neutrophilic leukemia with an associated V617F JAK2 tyrosine kinase mutation. Haematologica 2005;90:1696–1697.
  25. Lea NC, Lim Z, Westwood NB, Arno MJ, Gäken J, Mohamedali A, Mufti GJ: Presence of JAK2 V617F tyrosine kinase mutation as a myeloid-lineage-specific mutation in chronic neutrophilic leukaemia. Leukemia 2006;20:1324–1326.
  26. Ohyashiki K, Aota Y, Akahane D, Gotoh A, Miyazawa K, Kimura Y, Ohyashiki JH: The JAK2 V617F tyrosine kinase mutation in myelodysplastic syndromes (MDS) developing myelofibrosis indicates the myeloproliferative nature in a subset of MDS patients. Leukemia 2005;19:2359–2360.
  27. Johan MF, Goodeve AC, Bowen DT, Frew ME, Reilly JT: JAK2 V617F Mutation is uncommon in chronic myelomonocytic leukaemia. Br J Haematol 2005;130:968.
  28. Tono C, Xu G, Toki T, Takahashi Y, Sasaki S, Terui K, Ito E: JAK2 Val617Phe activating tyrosine kinase mutation in juvenile myelomonocytic leukemia. Leukemia 2005;19:1843–1844.
  29. Levine RL, Loriaux M, Huntly BJ, Loh ML, Beran M, Stoffregen E, Berger R, Clark JJ, Willis SG, Nguyen KT, Flores NJ, Estey E, Gattermann N, Armstrong S, Look AT, Griffin JD, Bernard OA, Heinrich MC, Gilliland DG, Druker B, Deininger MW: The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005;106:3377–3379.
  30. Horn T, Kremer M, Dechow T, Pfeifer WM, Geist B, Perker M, Duyster J, Quintanilla-Martinez L, Fend F: Detection of the activating JAK2 V617F mutation in paraffin-embedded trephine bone marrow biopsies of patients with chronic myeloproliferative diseases. J Mol Diagn 2006;8:299–304.
  31. Bock O, Busche G, Koop C, Schroter S, Buhr T, Kreipe H: Detection of the single hotspot mutation in the JH2 pseudokinase domain of Janus kinase 2 in bone marrow trephine biopsies derived from chronic myeloproliferative disorders. J Mol Diagn 2006;8:170–177.
  32. Kralovics R, Teo SS, Buser AS, Brutsche M, Tiedt R, Tichelli A, Passamonti F, Pietra D, Cazzola M, Skoda RC: Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood 2005;106:3374–3376.
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