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Table of Contents
Vol. 74, No. 2, 2007
Issue release date: June 2007
Section title: Review
Pathobiology 2007;74:81–88
(DOI:10.1159/000101707)

Chronic Myeloproliferative Disorders: The Role of Tyrosine Kinases in Pathogenesis, Diagnosis and Therapy

Macdonald D.a · Cross N.C.b
aDepartment of Haematology, Imperial College, London, and bWessex Regional Genetics Laboratory, University of Southampton, Salisbury Hospital, Salisbury, UK
email Corresponding Author

Abstract

The term chronic myeloproliferative disorders was originally used by Damashek to describe the link amongst a group of acquired blood diseases. Recent molecular genetic analysis has provided a scientific basis for this observation. Underlying myeloproliferative disorders are acquired abnormalities of tyrosine kinase genes. These may be chromosomal translocations resulting in the creation of a fusion kinase gene, examples of which include ABL, FGFR, and PDGFR as seen in disorders CML, 8p11 myeloproliferative syndrome, atypical CML and chronic eosinophilic leukaemia. The second group of tyrosine kinase abnormalities are point mutations in JAK2, a cytosolic TK. This abnormality is seen in 30–97% of cases of MPD with the phenotype PV, ET or CIMF.

© 2007 S. Karger AG, Basel


  

Key Words

  • Chronic myeloproliferative disorders
  • Leukaemia
  • Tyrosine kinase
  • JAK2
  • EMS
  • Polycythemia
  • FGFR1
  • PDGFR

References

  1. Dameshek W: Some speculations on the myeloproliferative syndromes. Blood 1951;6:372–375.
  2. Jaffe ES: World Health Organization: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press/Oxford University Press, 2001.
  3. Kaushansky K: Lineage-specific hematopoietic growth factors. N Engl J Med 2006;354:2034–2045.
  4. Alberts B: Molecular Biology of the Cell, ed 4. New York, Garland Science, 2002.
  5. Blume-Jensen P, Hunter T: Oncogenic kinase signalling. Nature 2001;411:355–365.
  6. Quintas-Cardama A, Cortes JE: Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc 2006;81:973–988.
  7. Melo JV, Deininger MW: Biology of chronic myelogenous leukemia-signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004;18:545–568, vii–viii.
  8. Macdonald D, Aguiar RC, Mason PJ, Goldman JM, Cross NC: A new myeloproliferative disorder associated with chromosomal translocations involving 8p11: a review. Leukemia 1995;9:1628–1630.
  9. Steer EJ, Cross NC: Myeloproliferative disorders with translocations of chromosome 5q31–35: role of the platelet-derived growth factor receptor β. Acta Haematol 2002;107:113–122.
  10. Inhorn RC, Aster JC, Roach SA, Slapak CA, Soiffer R, Tantravahi R, Stone RM: A syndrome of lymphoblastic lymphoma, eosinophilia, and myeloid hyperplasia/malignancy associated with t(8;13)(p11;q11): description of a distinctive clinicopathologic entity. Blood 1995;85:1881–1887.
  11. Gotlib J, Cross NC, Gilliland DG: Eosinophilic disorders: molecular pathogenesis, new classification, and modern therapy. Best Pract Res Clin Haematol 2006;19:535–569.
  12. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201–1214.
  13. Score J, Curtis C, Waghorn K, Stalder M, Jotterand M, Grand FH, Cross NC: Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia. Leukemia 2006;20:827–832.
  14. Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P, Williams IR, Gilliland DG, Cools J: Activation of FIP1L1-PDGFRα requires disruption of the juxtamembrane domain of PDGFRα and is FIP1L1-independent. Proc Natl Acad Sci USA 2006;103:8078–8083.
  15. Cools J, Stover EH, Gilliland DG: Detection of the FIP1L1-PDGFRA fusion in idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia. Methods Mol Med 2006;125:177–187.
  16. Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, Chase A, Chessells JM, Colombat M, Dearden CE, Dimitrijevic S, Mahon FX, Marin D, Nikolova Z, Olavarria E, Silberman S, Schultheis B, Cross NC, Goldman JM: Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor β. N Engl J Med 2002;347:481–487.
  17. Pardanani A, Brockman SR, Paternoster SF, Flynn HC, Ketterling RP, Lasho TL, Ho CL, Li CY, Dewald GW, Tefferi A: FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004;104:3038–3045.
  18. Chen J, Deangelo DJ, Kutok JL, Williams IR, Lee BH, Wadleigh M, Duclos N, Cohen S, Adelsperger J, Okabe R, Coburn A, Galinsky I, Huntly B, Cohen PS, Meyer T, Fabbro D, Roesel J, Banerji L, Griffin JD, Xiao S, Fletcher JA, Stone RM, Gilliland DG: PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. Proc Natl Acad Sci USA 2004;101:14479–14484.
  19. Skoda R, Prchal JT: Lessons from familial myeloproliferative disorders. Semin Hematol 2005;42:266–273.
  20. 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.
  21. Khwaja A: The role of Janus kinases in haemopoiesis and haematological malignancy. Br J Haematol 2006;134:366–384.
  22. 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.
  23. 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.
  24. Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, Cuker A, Wernig G, Moore S, Galinsky I, Deangelo DJ, Clark JJ, Lee SJ, Golub TR, Wadleigh M, Gilliland DG, Levine RL: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006;3:e270.
  25. Valent P, Akin C, Sperr WR, Mayerhofer M, Fodinger M, Fritsche-Polanz R, Sotlar K, Escribano L, Arock M, Horny HP, Metcalfe DD: Mastocytosis: pathology, genetics, and current options for therapy. Leuk Lymphoma 2005;46:35–48.
  26. Harrison CN, Green AR: Essential thrombocythaemia. Best Pract Res Clin Haematol 2006;19:439–453.
  27. McMullin MF, Bareford D, Campbell P, Green AR, Harrison C, Hunt B, Oscier D, Polkey MI, Reilly JT, Rosenthal E, Ryan K, Pearson TC, Wilkins B: Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 2005;130:174–195.
  28. Tefferi A: The diagnosis of polycythemia vera: new tests and old dictums. Best Pract Res Clin Haematol 2006;19:455–469.
  29. Tefferi A, Gilliland G: Classification of chronic myeloid disorders: from Dameshek towards a semi-molecular system. Best Pract Res Clin Haematol 2006;19:365–385.

  

Author Contacts

Donald Macdonald
Room 1L05, Charing Cross Hospital
Fulham Palace Road
London W6 8RF (UK)
Tel. +44 208 846 7122, Fax +44 208 846 7111, E-Mail d.h.macdonald@imperial.ac.uk

  

Article Information

Number of Print Pages : 8
Number of Figures : 3, Number of Tables : 1, Number of References : 29

  

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. Dameshek W: Some speculations on the myeloproliferative syndromes. Blood 1951;6:372–375.
  2. Jaffe ES: World Health Organization: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press/Oxford University Press, 2001.
  3. Kaushansky K: Lineage-specific hematopoietic growth factors. N Engl J Med 2006;354:2034–2045.
  4. Alberts B: Molecular Biology of the Cell, ed 4. New York, Garland Science, 2002.
  5. Blume-Jensen P, Hunter T: Oncogenic kinase signalling. Nature 2001;411:355–365.
  6. Quintas-Cardama A, Cortes JE: Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc 2006;81:973–988.
  7. Melo JV, Deininger MW: Biology of chronic myelogenous leukemia-signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004;18:545–568, vii–viii.
  8. Macdonald D, Aguiar RC, Mason PJ, Goldman JM, Cross NC: A new myeloproliferative disorder associated with chromosomal translocations involving 8p11: a review. Leukemia 1995;9:1628–1630.
  9. Steer EJ, Cross NC: Myeloproliferative disorders with translocations of chromosome 5q31–35: role of the platelet-derived growth factor receptor β. Acta Haematol 2002;107:113–122.
  10. Inhorn RC, Aster JC, Roach SA, Slapak CA, Soiffer R, Tantravahi R, Stone RM: A syndrome of lymphoblastic lymphoma, eosinophilia, and myeloid hyperplasia/malignancy associated with t(8;13)(p11;q11): description of a distinctive clinicopathologic entity. Blood 1995;85:1881–1887.
  11. Gotlib J, Cross NC, Gilliland DG: Eosinophilic disorders: molecular pathogenesis, new classification, and modern therapy. Best Pract Res Clin Haematol 2006;19:535–569.
  12. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201–1214.
  13. Score J, Curtis C, Waghorn K, Stalder M, Jotterand M, Grand FH, Cross NC: Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia. Leukemia 2006;20:827–832.
  14. Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P, Williams IR, Gilliland DG, Cools J: Activation of FIP1L1-PDGFRα requires disruption of the juxtamembrane domain of PDGFRα and is FIP1L1-independent. Proc Natl Acad Sci USA 2006;103:8078–8083.
  15. Cools J, Stover EH, Gilliland DG: Detection of the FIP1L1-PDGFRA fusion in idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia. Methods Mol Med 2006;125:177–187.
  16. Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, Chase A, Chessells JM, Colombat M, Dearden CE, Dimitrijevic S, Mahon FX, Marin D, Nikolova Z, Olavarria E, Silberman S, Schultheis B, Cross NC, Goldman JM: Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor β. N Engl J Med 2002;347:481–487.
  17. Pardanani A, Brockman SR, Paternoster SF, Flynn HC, Ketterling RP, Lasho TL, Ho CL, Li CY, Dewald GW, Tefferi A: FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004;104:3038–3045.
  18. Chen J, Deangelo DJ, Kutok JL, Williams IR, Lee BH, Wadleigh M, Duclos N, Cohen S, Adelsperger J, Okabe R, Coburn A, Galinsky I, Huntly B, Cohen PS, Meyer T, Fabbro D, Roesel J, Banerji L, Griffin JD, Xiao S, Fletcher JA, Stone RM, Gilliland DG: PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. Proc Natl Acad Sci USA 2004;101:14479–14484.
  19. Skoda R, Prchal JT: Lessons from familial myeloproliferative disorders. Semin Hematol 2005;42:266–273.
  20. 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.
  21. Khwaja A: The role of Janus kinases in haemopoiesis and haematological malignancy. Br J Haematol 2006;134:366–384.
  22. 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.
  23. 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.
  24. Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, Cuker A, Wernig G, Moore S, Galinsky I, Deangelo DJ, Clark JJ, Lee SJ, Golub TR, Wadleigh M, Gilliland DG, Levine RL: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006;3:e270.
  25. Valent P, Akin C, Sperr WR, Mayerhofer M, Fodinger M, Fritsche-Polanz R, Sotlar K, Escribano L, Arock M, Horny HP, Metcalfe DD: Mastocytosis: pathology, genetics, and current options for therapy. Leuk Lymphoma 2005;46:35–48.
  26. Harrison CN, Green AR: Essential thrombocythaemia. Best Pract Res Clin Haematol 2006;19:439–453.
  27. McMullin MF, Bareford D, Campbell P, Green AR, Harrison C, Hunt B, Oscier D, Polkey MI, Reilly JT, Rosenthal E, Ryan K, Pearson TC, Wilkins B: Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 2005;130:174–195.
  28. Tefferi A: The diagnosis of polycythemia vera: new tests and old dictums. Best Pract Res Clin Haematol 2006;19:455–469.
  29. Tefferi A, Gilliland G: Classification of chronic myeloid disorders: from Dameshek towards a semi-molecular system. Best Pract Res Clin Haematol 2006;19:365–385.