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Acute Leukemias

Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma

Leukemia volume 21, pages 1183–1188 (2007)Cite this article

Abstract

The FIP1L1-PDGFRA fusion gene has been described in patients with eosinophilia-associated myeloproliferative disorders (Eos-MPD). Here, we report on seven FIP1L1-PDGFRA-positive patients who presented with acute myeloid leukemia (AML, n=5) or lymphoblastic T-cell non-Hodgkin-lymphoma (n=2) in conjunction with AML or Eos-MPD. All patients were male, the median age was 58 years (range, 40–66). AML patients were negative for common mutations of FLT3, NRAS, NPM1, KIT, MLL and JAK2; one patient revealed a splice mutation of RUNX1 exon 7. Patients were treated with imatinib (100 mg, n=5; 400 mg, n=2) either as monotherapy (n=2), as maintenance treatment after intensive chemotherapy (n=3) or in overt relapse 43 and 72 months, respectively, after primary diagnosis and treatment of FIP1L1-PDGFRA-positive disease (n=2). All patients are alive, disease-free and in complete hematologic and complete molecular remission after a median time of 20 months (range, 9–36) on imatinib. The median time to achievement of complete molecular remission was 6 months (range, 1–14). We conclude that all eosinophilia-associated hematological malignancies should be screened for the presence of the FIP1L1-PDGFRA fusion gene as they are excellent candidates for treatment with tyrosine kinase inhibitors even if they present with an aggressive phenotype such as AML.

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References

  1. Bain BJ . Cytogenetic and molecular genetic aspects of eosinophilic leukaemias. Br J Haematol 2003; 122: 173–179.

    Article  PubMed  Google Scholar 

  2. Chusid MJ, Dale DC, West BC, Wolff SM . The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975; 54: 1–27.

    Article  CAS  Google Scholar 

  3. Weller PF, Bubley GJ . The idiopathic hypereosinophilic syndrome. Blood 1994; 83: 2759–2779.

    CAS  PubMed  Google Scholar 

  4. Kuroda J, Kimura S, Akaogi T, Hayashi H, Yamano T, Sasai Y et al. Myelodysplastic syndrome with clonal eosinophilia accompanied by eosinophilic pulmonary interstitial infiltration. Acta Haematol 2000; 104: 119–123.

    Article  CAS  PubMed  Google Scholar 

  5. Macdonald D, Reiter A, Cross NC . The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol 2002; 107: 101–107.

    Article  CAS  PubMed  Google Scholar 

  6. Steer EJ, Cross NC . Myeloproliferative disorders with translocations of chromosome 5q31–35: role of the platelet-derived growth factor receptor beta. Acta Haematol 2002; 107: 113–122.

    Article  CAS  PubMed  Google Scholar 

  7. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J et al. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Gilliland G, Cools J, Stover EH, Wlodarska I, Marynen P . FIP1L1-PDGFRalpha in hypereosinophilic syndrome and mastocytosis. Hematol J 2004; 5 (Suppl 3): S133–S137.

    Article  CAS  PubMed  Google Scholar 

  9. Pardanani A, Ketterling RP, Brockman SR, Flynn HC, Paternoster SF, Shearer BM et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 2003; 102: 3093–3096.

    Article  CAS  PubMed  Google Scholar 

  10. Pardanani A, Reeder T, Porrata LF, Li CY, Tazelaar HD, Baxter EJ et al. Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 2003; 101: 3391–3397.

    Article  CAS  PubMed  Google Scholar 

  11. Tefferi A . Modern diagnosis and treatment of primary eosinophilia. Acta Haematol 2005; 114: 52–60.

    Article  CAS  PubMed  Google Scholar 

  12. Pardanani A, Ketterling RP, Li CY, Patnaik MM, Wolanskyj AP, Elliott MA et al. FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res 2006; 30: 965–970.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    CAS  PubMed  Google Scholar 

  14. Robyn J, Lemery S, McCoy JP, Kubofcik J, Kim YJ, Pack S et al. Multilineage involvement of the fusion gene in patients with FIP1L1/PDGFRA-positive hypereosinophilic syndrome. Br J Haematol 2006; 132: 286–292.

    Article  CAS  PubMed  Google Scholar 

  15. Nakao M, Janssen JW, Erz D, Seriu T, Bartram CR . Tandem duplication of the FLT3 gene in acute lymphoblastic leukemia: a marker for the monitoring of minimal residual disease. Leukemia 2000; 14: 522–524.

    Article  CAS  PubMed  Google Scholar 

  16. Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T et al. Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia 2000; 14: 796–804.

    Article  CAS  PubMed  Google Scholar 

  17. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59–66.

    CAS  PubMed  Google Scholar 

  18. Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005; 106: 3733–3739.

    Article  CAS  PubMed  Google Scholar 

  19. Nakao M, Janssen JW, Seriu T, Bartram CR . Rapid and reliable detection of N-ras mutations in acute lymphoblastic leukemia by melting curve analysis using LightCycler technology. Leukemia 2000; 14: 312–315.

    Article  CAS  PubMed  Google Scholar 

  20. Miyoshi H, Ohira M, Shimizu K, Mitani K, Hirai H, Imai T et al. Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia. Nucleic Acids Res 1995; 23: 2762–2769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Score J, Curtis C, Waghorn K, Stalder M, Jotterand M, Grand FH et al. Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia. Leukemia 2006; 20: 827–832.

    Article  CAS  PubMed  Google Scholar 

  22. Piccaluga PP, Agostinelli C, Zinzani PL, Baccarani M, Dalla FR, Pileri SA . Expression of platelet-derived growth factor receptor alpha in peripheral T-cell lymphoma not otherwise specified. Lancet Oncol 2005; 6: 440.

    Article  PubMed  Google Scholar 

  23. Cross NC, Reiter A . Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia 2002; 16: 1207–1212.

    Article  CAS  PubMed  Google Scholar 

  24. Giles FJ, Cortes JE, Kantarjian HM . Targeting the kinase activity of the BCR-ABL fusion protein in patients with chronic myeloid leukemia. Curr Mol Med 2005; 5: 615–623.

    Article  CAS  PubMed  Google Scholar 

  25. von Bubnoff N, Sandherr M, Schlimok G, Andreesen R, Peschel C, Duyster J . Myeloid blast crisis evolving during imatinib treatment of an FIP1L1-PDGFR alpha-positive chronic myeloproliferative disease with prominent eosinophilia. Leukemia 2005; 19: 286–287.

    Article  CAS  PubMed  Google Scholar 

  26. Vandenberghe P, Wlodarska I, Michaux L, Zachee P, Boogaerts M, Vanstraelen D et al. Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia 2004; 18: 734–742.

    Article  CAS  PubMed  Google Scholar 

  27. Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD . Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 2007; 109: 431–448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Suzuki M, Abe A, Kiyoi H, Murata M, Ito Y, Shimada K et al. Mutations of N-RAS, FLT3 and p53 genes are not involved in the development of acute leukemia transformed from myeloproliferative diseases with JAK2 mutation. Leukemia 2006; 20: 1168–1169.

    Article  CAS  PubMed  Google Scholar 

  29. Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B et al. The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res 2005; 65: 2662–2667.

    Article  CAS  PubMed  Google Scholar 

  30. Roche-Lestienne C, Lepers S, Soenen-Cornu V, Kahn JE, Lai JL, Hachulla E et al. Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics. Leukemia 2005; 19: 792–798.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    CAS  PubMed  Google Scholar 

  32. Cools J, Stover EH, Boulton CL, Gotlib J, Legare RD, Amaral SM et al. PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha-induced myeloproliferative disease. Cancer Cell 2003; 3: 459–469.

    Article  CAS  PubMed  Google Scholar 

  33. Lierman E, Folens C, Stover EH, Mentens N, Van Miegroet H, Scheers W et al. Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant. Blood 2006; 108: 1374–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the ‘Deutsche José Carreras Leukämie-Stiftung e.V.’ (CW, AR, Grant no. DJCLS R06/02), Germany, the Leukaemia Research Fund, United Kingdom, the Competence Network ‘Acute and chronic leukemias’, sponsored by the German Bundesministerium für Bildung und Forschung (Projektträger Gesundheitsforschung; DLR e.V. – 01GI9980/6) and the ‘European LeukemiaNet’ within the 6th European Community Framework Programme for Research and Technological Development.

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Authors and Affiliations

  1. III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany

    G Metzgeroth, C Walz, H Popp, P Erben, J Mix, M C Müller, R Hehlmann, A Hochhaus & A Reiter

  2. Human Genetics Division, Wessex Regional Genetics Laboratory, University of Southampton School of Medicine, Salisbury, UK

    J Score & N C P Cross

  3. Institut für Humangenetik, Universität Kiel, Kiel, Germany

    R Siebert

  4. MLL, Münchner Leukämie Labor, München, Germany

    S Schnittger, C Haferlach, T Haferlach & F Diecker

  5. Innere Medizin III, Universitätsklinik und Poliklinik, Ulm, Germany

    H Beneke & H Döhner

  6. Onkologische Schwerpunktpraxis, Leer, Germany

    L Müller

  7. II. Medizinische Klinik, Städtisches Klinikum, Oldenburg, Germany

    F Del Valle

  8. Zentrum für Innere Medizin, Robert-Bosch Krankenhaus, Stuttgart, Germany

    W E Aulitzky

  9. Internistische Gemeinschaftspraxis, Schloßmühlendamm, Hamburg, Germany

    G Wittkowsky

  10. Hämatologische Abteilung des Onkologischen Zentrums, Asklepios Klinik St. Georg, Hamburg, Germany

    N Schmitz

  11. Institut für Hämatopathologie Hamburg, Hamburg, Germany

    C Schulte

  12. Pathologisches Institut der Universität Würzburg, Würzburg, Germany

    K Müller-Hermelink

  13. Cancer Sciences Division, Department of Molecular Pathology, University of Southampton School of Medicine, Southampton, UK

    E Hodges

  14. St. John's Institute of Dermatology, St. Thomas' Hospital, London, UK

    S J Whittaker

  15. Novartis Pharma, Nürnberg, Germany

    P Schuld

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  1. G Metzgeroth
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  16. G Wittkowsky
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  17. N Schmitz
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  18. C Schulte
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  27. A Reiter
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Correspondence to A Reiter.

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Metzgeroth, G., Walz, C., Score, J. et al. Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma. Leukemia 21, 1183–1188 (2007). https://doi.org/10.1038/sj.leu.2404662

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  • DOI: https://doi.org/10.1038/sj.leu.2404662

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