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Chronic Myeloproliferative Neoplasias

The molecular anatomy of the FIP1L1-PDGFRA fusion gene

Abstract

The FIP1L1-PDGFRA fusion gene is a recurrent molecular abnormality in patients with eosinophilia-associated myeloproliferative neoplasms. We characterized FIP1L1-PDGFRA junction sequences from 113 patients at the mRNA (n=113) and genomic DNA (n=85) levels. Transcript types could be assigned in 109 patients as type A (n=50, 46%) or B (n=47, 43%), which were created by cryptic acceptor splice sites in different introns of FIP1L1 (type A) or within PDGFRA exon 12 (type B). We also characterized a new transcript type C (n=12, 11%) in which both genomic breakpoints fell within coding sequences creating a hybrid exon without use of a cryptic acceptor splice site. The location of genomic breakpoints within PDGFRA and the availability of AG splice sites determine the transcript type and restrict the FIP1L1 exons used for the creation of the fusion. Stretches of overlapping sequences were identified at the genomic junction site, suggesting that the FIP1L1-PDGFRA fusion is created by illegitimate non-homologous end-joining. Statistical analyses provided evidence for clustering of breakpoints within FIP1L1 that may be related to DNA- or chromatin-related structural features. The variability in the anatomy of the FIP1L1-PDGFRA fusion has important implications for strategies to detect the fusion at diagnosis or for monitoring response to treatment.

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References

  1. 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  Google Scholar 

  2. 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  Google Scholar 

  3. 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 therapy. Blood 2003; 102: 3093–3096.

    Article  CAS  Google Scholar 

  4. Pardanani A, Brockman SR, Paternoster SF, Flynn HC, Ketterling RP, Lasho TL et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004; 104: 3038–3045.

    Article  CAS  Google Scholar 

  5. Martinelli G, Malagola M, Ottaviani E, Rosti G, Trabacchi E, Baccarani M . Imatinib mesylate can induce complete molecular remission in FIP1L1-PDGFR-a positive idiopathic hypereosinophilic syndrome. Haematologica 2004; 89: 236–237.

    PubMed  Google Scholar 

  6. Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G et al. Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA positive chronic eosinophilic leukemia. Blood 2007; 109: 4635–4640.

    Article  CAS  Google Scholar 

  7. Baccarani M, Cilloni D, Rondoni M, Ottaviani F, Messa F, Merante S et al. Imatinib mesylate induces complete and durable responses in all patients with the FIP1L1-PDGFRa positive hypereosinophilic syndrome. Results of a multicenter study. Haematologica 2007; 92: 1173–1179.

    Article  CAS  Google Scholar 

  8. Metzgeroth G, Walz C, Score J, Siebert R, Schnittger S, Haferlach C et al. Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma. Leukemia 2007; 21: 1183–1188.

    Article  CAS  Google Scholar 

  9. Metzgeroth G, Walz C, Erben P, Popp H, Schmitt-Graeff AH, Haferlach C et al. Safety and efficacy of imatinib in chronic eosinophilic leukemia and hypereosinophilic syndrome—a phase-II study. Br J Haematol 2008 143: 707–715.

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. Loader CR . Large deviation approximations to the distribution of scan statistics. Adv Appl Probab 1991; 23: 751–771.

    Article  Google Scholar 

  12. Segal MR, Wiemels JL . Clustering of translocation breakpoints. J Am Stat Assoc 2002; 97: 66–76.

    Article  Google Scholar 

  13. Frisch M, Frech K, Klingenhoff A, Cartharius K, Liebich I, Werner T . In silico prediction of scaffold/matrix attachment regions in large genomic sequences. Genome Res 2002; 12: 349–354.

    Article  CAS  Google Scholar 

  14. Liebich I, Bode J, Reuter I, Wingender E . Evaluation of sequence motifs found in scaffold/matrix-attached regions (S/MARs). Nucleic Acids Res 2002; 30: 3433–3442.

    Article  CAS  Google Scholar 

  15. Baxter EJ, Hochhaus A, Bolufer P, Reiter A, Fernandez JM, Senent L et al. The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. Hum Mol Genet 2002; 11: 1391–1397.

    Article  CAS  Google Scholar 

  16. Curtis CE, Grand FH, Musto P, Clark A, Murphy J, Perla G et al. Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia. Br J Haematol 2007; 138: 77–81.

    Article  CAS  Google Scholar 

  17. Walz C, Curtis C, Schnittger S, Schultheis B, Metzgeroth G, Schoch C et al. Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene. Genes Chromosomes Cancer 2006; 45: 950–956.

    Article  CAS  Google Scholar 

  18. Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P et al. Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent. Proc Natl Acad Sci USA 2006; 103: 8078–8083.

    Article  CAS  Google Scholar 

  19. Kondo T, Mori A, Darmanin S, Hashino S, Tanaka J, Asaka M . The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia. Haematologica 2008; 93: 1414–1416.

    Article  CAS  Google Scholar 

  20. Bowater R, Doherty AJ . Making ends meet: repairing breaks in bacterial DNA by non-homologous end-joining. PLoS Genet 2006; 2: e8.

    Article  Google Scholar 

  21. Hefferin ML, Tomkinson AE . Mechanism of DNA double-strand break repair by non-homologous end joining. DNA Repair (Amst) 2005; 4: 639–648.

    Article  CAS  Google Scholar 

  22. Wiemels JL, Alexander FE, Cazzaniga G, Biondi A, Mayer SP, Greaves M . Microclustering of TEL-AML1 translocation breakpoints in childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer 2000; 29: 219–228.

    Article  CAS  Google Scholar 

  23. Gillert E, Leis T, Repp R, Reichel M, Hosch A, Breitenlohner I et al. A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells. Oncogene 1999; 18: 4663–4671.

    Article  CAS  Google Scholar 

  24. Reichel M, Gillert E, Nilson I, Siegler G, Greil J, Fey GH et al. Fine structure of translocation breakpoints in leukemic blasts with chromosomal translocation t(4;11): the DNA damage-repair model of translocation. Oncogene 1998; 17: 3035–3044.

    Article  CAS  Google Scholar 

  25. Nebral K, Schmidt HH, Haas OA, Strehl S . NUP98 is fused to topoisomerase (DNA) IIbeta 180 kDa (TOP2B) in a patient with acute myeloid leukemia with a new t(3;11)(p24;p15). Clin Cancer Res 2005; 11: 6489–6494.

    Article  CAS  Google Scholar 

  26. Reiter A, Saussele S, Grimwade D, Wiemels JL, Segal MR, Lafage-Pochitaloff M et al. Genomic anatomy of the specific reciprocal translocation t(15;17) in acute promyelocytic leukemia. Genes Chromosomes Cancer 2003; 36: 175–188.

    Article  CAS  Google Scholar 

  27. van der Reijden BA, Dauwerse HG, Giles RH, Jagmohan-Changur S, Wijmenga C, Liu PP et al. Genomic acute myeloid leukemia-associated inv(16)(p13q22) breakpoints are tightly clustered. Oncogene 1999; 18: 543–550.

    Article  CAS  Google Scholar 

  28. Xiao Z, Greaves MF, Buffler P, Smith MT, Segal MR, Dicks BM et al. Molecular characterization of genomic AML1-ETO fusions in childhood leukemia. Leukemia 2001; 15: 1906–1913.

    Article  CAS  Google Scholar 

  29. Wiemels JL, Greaves M . Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. Cancer Res 1999; 59: 4075–4082.

    CAS  Google Scholar 

  30. Zhang JG, Goldman JM, Cross NC . Characterization of genomic BCR-ABL breakpoints in chronic myeloid leukaemia by PCR. Br J Haematol 1995; 90: 138–146.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the ‘Deutsche José Carreras Leukämie-Stiftung eV—DJCLS R06/02 and H03/01, Germany, Leukaemia Research Fund, UK, the Competence Network ‘Acute and Chronic Leukemias’, sponsored by the German Bundesministerium für Bildung und Forschung (Projektträger Gesundheitsforschung; DLR eV—01GI9980/6) and the ‘European LeukemiaNet’ within the 6th European Community Framework Programme for Research and Technological Development. R-FY and JLW were supported by NCI-CA89032. GM was supported by FIRB2006 and AIRC.

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Correspondence to A Reiter.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Walz, C., Score, J., Mix, J. et al. The molecular anatomy of the FIP1L1-PDGFRA fusion gene. Leukemia 23, 271–278 (2009). https://doi.org/10.1038/leu.2008.310

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