Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia (original) (raw)

Nature Genetics volume 36, pages 1084–1089 (2004)Cite this article

Abstract

In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified1,2,3. Here we describe the extrachromosomal (episomal)4 amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib7,8. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression1 and deletion of CDKN2A9, consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib.

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References

  1. Ferrando, A.A. et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1, 75–87 (2002).
    Article CAS Google Scholar
  2. Pui, C.H., Relling, M.V. & Downing, J.R. Acute lymphoblastic leukemia. N. Engl. J. Med. 350, 1535–1548 (2004).
    Article CAS Google Scholar
  3. Paietta, E. et al. Activating FLT3 mutations in CD117/KIT positiveT-cell acute lymphoblastic leukemias. Blood 104, 558–560 (2004).
    Article CAS Google Scholar
  4. Maurer, B.J., Lai, E., Hamkalo, B.A., Hood, L. & Attardi, G. Novel submicroscopic extrachromosomal elements containing amplified genes in human cells. Nature 327, 434–437 (1987).
    Article CAS Google Scholar
  5. de Klein, A. et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300, 765–767 (1982).
    Article CAS Google Scholar
  6. von Lindern, M. et al. The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA. Mol. Cell Biol. 12, 1687–1697 (1992).
    Article CAS Google Scholar
  7. Capdeville, R., Buchdunger, E., Zimmermann, J. & Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat. Rev. Drug Discov. 1, 493–502 (2002).
    Article CAS Google Scholar
  8. Druker, B.J. et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344, 1038–1042 (2001).
    Article CAS Google Scholar
  9. Hebert, J., Cayuela, J.M., Berkeley, J. & Sigaux, F. Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias. Blood 84, 4038–4044 (1994).
    CAS PubMed Google Scholar
  10. de Klein, A. et al. bcr rearrangement and translocation of the c-abl oncogene in Philadelphia positive acute lymphoblastic leukemia. Blood 68, 1369–1375 (1986).
    CAS PubMed Google Scholar
  11. Hahn, P.J. Molecular biology of double-minute chromosomes. Bioessays 15, 477–484 (1993).
    Article CAS Google Scholar
  12. Carroll, S.M. et al. Double minute chromosomes can be produced from precursors derived from a chromosomal deletion. Mol. Cell Biol. 8, 1525–1533 (1988).
    Article CAS Google Scholar
  13. Kraemer, D., Wozniak, R.W., Blobel, G. & Radu, A. The human CAN protein, a putative oncogene product associated with myeloid leukemogenesis, is a nuclear pore complex protein that faces the cytoplasm. Proc. Natl. Acad. Sci. USA 91, 1519–1523 (1994).
    Article CAS Google Scholar
  14. Golub, T.R. et al. Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. Mol. Cell Biol. 16, 4107–4116 (1996).
    Article CAS Google Scholar
  15. Oda, T. et al. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J. Biol. Chem. 269, 22925–22928 (1994).
    CAS PubMed Google Scholar
  16. Nieborowska-Skorska, M., Slupianek, A. & Skorski, T. Progressive changes in the leukemogenic signaling in BCR/ABL-transformed cells. Oncogene 19, 4117–4124 (2000).
    Article CAS Google Scholar
  17. Kelly, L.M. & Gilliland, D.G. Genetics of myeloid leukemias. Annu. Rev. Genomics Hum. Genet. 3, 179–198 (2002).
    Article CAS Google Scholar
  18. Nagel, S., Kaufmann, M., Drexler, H.G. & MacLeod, R.A. The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Cancer Res. 63, 5329–5334 (2003).
    CAS PubMed Google Scholar
  19. Barber, K.E. et al. Amplification of the ABL gene in T-cell acute lymphoblastic leukemia. Leukemia 18, 1153–1156 (2004).
    Article CAS Google Scholar
  20. Cools, 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. 348, 1201–1214 (2003).
    Article CAS Google Scholar
  21. Mitelman, F. ISCN(1995): Guidelines for Cancer Cytogenetics. Supplement to an International System for Human Nomenclature (Karger, Basel, 1995).
    Google Scholar
  22. Dierlamm, J. et al. Successful use of the same slide for consecutive fluorescence in situ hybridization experiments. Genes Chromosomes Cancer 16, 261–264 (1996).
    Article CAS Google Scholar
  23. Fiegler, H. et al. DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 36, 361–374 (2003).
    Article CAS Google Scholar
  24. Van Buggenhout, G. et al. The mild Wolf-Hirschhorn syndrome: microarray CGH analysis of atypical 4p16.3 deletions enables refinement of the genotype-phenotype map. J. Med. Genet. 41, 691–698 (2004).
    Article CAS Google Scholar
  25. Fornerod, M. et al. Relocation of the carboxyterminal part of CAN from the nuclear envelope to the nucleus as a result of leukemia-specific chromosome rearrangements. Oncogene 10, 1739–1748 (1995).
    CAS PubMed Google Scholar
  26. Cools, J. et al. Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13). Blood 94, 1820–1824 (1999).
    CAS PubMed Google Scholar
  27. Bene, M.C. et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 9, 1783–1786 (1995).
    CAS PubMed Google Scholar

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Acknowledgements

This text presents research results of the Belgian program of Interuniversity Poles of attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming. The scientific responsibility is assumed by the authors. The authors thank the Mapping Core and Map Finishing groups of the Wellcome Trust Sanger Institute for initial clone supply and verification. This work was supported by grants from the Belgian Federation against Cancer (J.C.), the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (P.M.) and the National Institutes of Health (A.T.L., D.G.G.). J.C. is a postdoctoral researcher and P.V. is a clinical investigator of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. C.G. received a grant from the Belgian Hematological Society and a grant from the Franqui-De Roover Foundation (Salus Sanguinis). D.G.G. is an Investigator of the Howard Hughes Medical Institute and a Doris Duke Distinguished Clinical Scientist.

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Author notes

  1. C. Graux and J. Cools: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, University of Leuven, Leuven, Belgium
    C. Graux, J. Cools, C. Melotte, J.R. Vermeesch, M. Stul, N. Mentens, R. Somers, P. Vandenberghe, I. Wlodarska, Peter Marynen & Anne Hagemeijer
  2. Department of Hematology, University of Leuven, Leuven, Belgium
    C. Graux, N. Boeckx & P. Vandenberghe
  3. Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium
    J. Cools, N. Mentens, R. Somers & Peter Marynen
  4. German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
    H. Quentmeier, R.A.F. MacLeod & H.G. Drexler
  5. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
    A. Ferrando, R. Levine, A.T. Look & D.G. Gilliland
  6. Microarray Facility, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium
    B. Dutta
  7. Department of Hematology, Cliniques universitaires UCL de Mont-Godinne, Yvoir, Brussels, Belgium
    A. Bosly
  8. Department of Medical Genetics, Erasme Hospital, Free University of Brussels, Brussels, Belgium
    P. Heimann
  9. Department of Pediatric Hemato-oncology, University of Leuven, Leuven, Belgium
    A. Uyttebroeck
  10. Brigham and Women's Hospital, Boston, Massachusetts, USA
    D.G. Gilliland
  11. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA
    D.G. Gilliland
  12. St. Luc, Brussels, Belgium
    L. Michaux

Authors

  1. C. Graux
  2. J. Cools
  3. C. Melotte
  4. H. Quentmeier
  5. A. Ferrando
  6. R. Levine
  7. J.R. Vermeesch
  8. M. Stul
  9. B. Dutta
  10. N. Boeckx
  11. A. Bosly
  12. P. Heimann
  13. A. Uyttebroeck
  14. N. Mentens
  15. R. Somers
  16. R.A.F. MacLeod
  17. H.G. Drexler
  18. A.T. Look
  19. D.G. Gilliland
  20. L. Michaux
  21. P. Vandenberghe
  22. I. Wlodarska
  23. Peter Marynen
  24. Anne Hagemeijer

Corresponding authors

Correspondence toPeter Marynen or Anne Hagemeijer.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The episomes contain both NUP214 and ABL1, and are not detected by standard cytogenetics analysis. (PDF 22 kb)

Supplementary Fig. 2

Southern blot analysis confirms the increased ABL1 copy number. (PDF 62 kb)

Supplementary Fig. 3

Dose-dependent inhibition of NUP214-ABL1 phosphorylation by imatinib in the PEER and BE-13 cell lines. (PDF 56 kb)

Supplementary Table 1

List of the 26 T-ALL cell lines screened by RT-PCR for presence of the NUP214-ABL1 fusion. (PDF 7 kb)

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Graux, C., Cools, J., Melotte, C. et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia.Nat Genet 36, 1084–1089 (2004). https://doi.org/10.1038/ng1425

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