Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Recurrent SETBP1 mutations in atypical chronic myeloid leukemia

Nature Genetics volume 45, pages 18–24 (2013)Cite this article

Subjects

Abstract

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distribution of alterations on the SETBP1 protein.
Figure 2: Mutation profile of 61 aCML cases for a panel of 15 genes.
Figure 3: Clinical findings in cases with wild-type and mutated SETBP1.
Figure 4: Interaction between β-TrCP1 and SETBP1.
Figure 5: Effects of the SETBP1 p.Gly870Ser alteration on SETBP1 and SET protein expression, PP2A activity and cell growth.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Sequence Read Archive

Referenced accessions

NCBI Reference Sequence

References

  1. Vardiman, J.W. et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114, 937–951 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Nowell, P.C. & Hungerford, D.A. A minute chromosome in human chronic granulocytic leukemia. Science 132, 1497–1497 (1960).

    Google Scholar 

  3. Kurzrock, R. et al. BCR rearrangement–negative chronic myelogenous leukemia revisited. J. Clin. Oncol. 19, 2915–2926 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Druker, B.J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Rebora, P. et al. Are chronic myeloid leukemia patients more at risk for second malignancies? A population-based study. Am. J. Epidemiol. 172, 1028–1033 (2010).

    Article  PubMed  Google Scholar 

  6. Gambacorti-Passerini, C. et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J. Natl. Cancer Inst. 103, 553–561 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Goldman, J.M. Chronic myeloid leukemia: a historical perspective. Semin. Hematol. 47, 302–311 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Shah, S.P. et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N. Engl. J. Med. 360, 2719–2729 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Tiacci, E. et al. BRAF mutations in hairy-cell leukemia. N. Engl. J. Med. 364, 2305–2315 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mardis, E.R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Longo, D.L. Tumor heterogeneity and personalized medicine. N. Engl. J. Med. 366, 956–957 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Stratton, M.R., Campbell, P.J. & Futreal, P.A. The cancer genome. Nature 458, 719–724 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Godley, L.A. Profiles in leukemia. N. Engl. J. Med. 366, 1152–1153 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Ernst, T. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42, 722–726 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Minakuchi, M. et al. Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET. Eur. J. Biochem. 268, 1340–1351 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kumar, P., Henikoff, S. & Ng, P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Piazza, R. et al. FusionAnalyser: a new graphical, event-driven tool for fusion rearrangements discovery. Nucleic Acids Res. 40, e123 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dinkel, H. et al. ELM—the database of eukaryotic linear motifs. Nucleic Acids Res. 40, D242–D251 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Winston, J.T. et al. The SCFβ-TRCP–ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro. Genes Dev. 13, 270–283 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Reiter, A., Invernizzi, R., Cross, N.C.P. & Cazzola, M. Molecular basis of myelodysplastic/myeloproliferative neoplasms. Haematologica 94, 1634–1638 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cristóbal, I. et al. SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia. Blood 115, 615–625 (2010).

    Article  PubMed  Google Scholar 

  23. Panagopoulos, I. et al. Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12). Br. J. Haematol. 136, 294–296 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Shah, S.P. et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395–399 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Manfredini, R. et al. The kinetic status of hematopoietic stem cell subpopulations underlies a differential expression of genes involved in self-renewal, commitment, and engraftment. Stem Cells 23, 496–506 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Oakley, K. et al. Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10. Blood 119, 6099–6108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Neviani, P. et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell 8, 355–368 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Janssens, V., Goris, J. & Van Hoof, C. PP2A: the expected tumor suppressor. Curr. Opin. Genet. Dev. 15, 34–41 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Liu, X., Sun, Y., Weinberg, R.A. & Lodish, H.F. Ski/Sno and TGF-β signaling. Cytokine Growth Factor Rev. 12, 1–8 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Hoischen, A. et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat. Genet. 42, 483–485 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Mundy, G.R. The effects of Tgf-β on bone. Ciba Found. Symp. 157, 137–143 (1991).

    CAS  PubMed  Google Scholar 

  32. Lehman, A.M. et al. Schinzel-Giedion syndrome: report of splenopancreatic fusion and proposed diagnostic criteria. Am. J. Med. Genet. A 146A, 1299–1306 (2008).

    Article  PubMed  Google Scholar 

  33. Cross, N.C. Histone modification defects in developmental disorders and cancer. Oncotarget 3, 3–4 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Goecks, J., Nekrutenko, A. & Taylor, J. Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences. Genome Biol. 11, R86 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Blankenberg, D. et al. Galaxy: a web-based genome analysis tool for experimentalists. Curr. Protoc. Mol. Biol. Chapter 19 Unit 19.10.1–21.

  37. Giardine, B. et al. Galaxy: a platform for interactive large-scale genome analysis. Genome Res. 15, 1451–1455 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    PubMed  PubMed Central  Google Scholar 

  39. Score, J. et al. Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Blood 119, 1208–1213 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Grand, F.H. et al. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 113, 6182–6192 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Ernst, T. et al. Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms. Haematologica 95, 1473–1480 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Randles, R.H. & Wolfe, D.A. Introduction to the Theory of Nonparametric Statistics (Wiley, 1979).

  43. Marubini, E. & Valsecchi,, M.G. Analyzing Survival Data from Clinical Trials and Observational Studies (ed. Sons, J.W.) (Chichester, UK, 1995).

  44. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pear, W.S. et al. Efficient and rapid induction of a chronic myelogenous leukemia–like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 92, 3780–3792 (1998).

    CAS  PubMed  Google Scholar 

  46. le Coutre, P. et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J. Natl. Cancer Inst. 91, 163–168 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Trapnell, C., Pachter, L. & Salzberg, S.L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S.L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Robinson, J.T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Xu, G. et al. SAMMate: a GUI tool for processing short read alignments in SAM/BAM format. Source Code Biol. Med. 6, 2 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Mortazavi, A., Williams, B.A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621–628 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Tarazona, S., Garcia-Alcalde, F., Dopazo, J., Ferrer, A. & Conesa, A. Differential expression in RNA-seq: a matter of depth. Genome Res. 21, 2213–2223 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We kindly acknowledge the contributions of S. Mori in the preparation of this manuscript, M. Viltadi for technical help and C. Cecchetti, Z. Sortino and C. Rizzo for clinical sample management. We thank M. Vogel for her critical reading of the manuscript. This work was supported by AIRC 2010 (IG-10092 to C.G.-P.); PRIN program (20084XBENM_004 to R.P.); Fondazione Cariplo (2009-2667 to C.G.-P.); the Lombardy Region (ID-16871 and ID14546A to C.G.-P. and FSE Dote Ricercatori 16-AR to S.R.); Leukaemia and Lymphoma Research (UK) grants (to N.C.P.C. and J.B.); the Basic Research Program of the Korea Research Foundation (R21-2007-000-10041-0 to D.-W.K.) (2007); and Mildred Scheel Stiftung fuer Krebsforschung (Deutsche Krebshilfe, Germany, grant 109590 to N.W.).

Author information

Author notes

  1. Hyun Gyung Jang & Valeria Fantin

    Present address: Present addresses: Ariad Pharmaceutical, Cambridge, Massachusetts, USA (H.G.J.) and Tumor Cell Biology, Pfizer, La Jolla, California, USA (V.F.).,

  2. Rocco Piazza, Simona Valletta and Sara Redaelli: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Health Sciences, University of Milano–Bicocca, Monza, Italy

    Rocco Piazza, Simona Valletta, Sara Redaelli, Roberta Spinelli, Alessandra Pirola, Laura Antolini, Luca Mologni, Carla Donadoni, Greta P De Martini, Vera Magistroni, Enrico Maria Pogliani & Carlo Gambacorti-Passerini

  2. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK

    Nils Winkelmann, Andrew J Chase, William J Tapper & Nicholas C P Cross

  3. Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    Nils Winkelmann

  4. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Elli Papaemmanuil, Graham R Bignell & Peter J Campbell

  5. Munich Leukemia Laboratory (MLL), Munich, Germany

    Susanne Schnittger & Torsten Haferlach

  6. Department of Hematology, Catholic University, Seoul, Korea

    Dong-Wook Kim

  7. Leukaemia & Lymphoma Research Molecular Hematology Unit, John Radcliffe Hospital, Oxford, UK

    Jacqueline Boultwood

  8. Immunotransfusional Unit, San Gerardo Hospital, Monza, Italy

    Fabio Rossi

  9. M Tettamanti Research Center, Pediatric Clinic University of Milano–Bicocca, Monza, Italy

    Giuseppe Gaipa

  10. Anatomia Patologica II, Laboratorio Oncologia Molecolare, Centro di Ricerca in Medicina Sperimentale (CeRMS), Azienda Ospedaliera San Giovanni Battista di Torino, Torino, Italy

    Paola Francia di Celle

  11. Agios Pharmaceuticals, Cambridge, Massachusetts, USA

    Hyun Gyung Jang & Valeria Fantin

  12. Hematology Unit, San Gerardo Hospital, Monza, Italy

    Enrico Maria Pogliani

  13. Faculty of Medicine, University of Southampton, Southampton, UK

    Andrew J Chase, William J Tapper & Nicholas C P Cross

  14. Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy

    Carlo Gambacorti-Passerini

Authors
  1. Rocco Piazza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simona Valletta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nils Winkelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara Redaelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Roberta Spinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alessandra Pirola
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laura Antolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luca Mologni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carla Donadoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Elli Papaemmanuil
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Susanne Schnittger
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dong-Wook Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jacqueline Boultwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Fabio Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Giuseppe Gaipa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Greta P De Martini
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Paola Francia di Celle
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hyun Gyung Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Valeria Fantin
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Graham R Bignell
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Vera Magistroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Torsten Haferlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Enrico Maria Pogliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Peter J Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Andrew J Chase
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. William J Tapper
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Nicholas C P Cross
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Carlo Gambacorti-Passerini
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.P., S.V., N.W., S.R., R.S., A.P., L.M., C.D., E.P., P.F.d.C., H.G.J., V.F., G.R.B., V.M., P.J.C. and A.J.C. performed the experiments. R.P., S.V., S.R., R.S., L.A., F.R., A.J.C., W.J.T. and N.C.P.C. performed data analysis. S.S., D.-W.K., J.B., G.G., G.P.D.M., T.H., P.J.C., E.M.P. and N.C.P.C. contributed reagents, materials and analysis tools. R.P. and C.G.-P. wrote the first draft of the manuscript. L.A. performed statistical analysis. N.C.P.C. and C.G.-P. supervised research. C.G.-P. initiated the project. All coauthors contributed to the final version of the manuscript.

Corresponding author

Correspondence to Carlo Gambacorti-Passerini.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1–6 (PDF 3540 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Piazza, R., Valletta, S., Winkelmann, N. et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet 45, 18–24 (2013). https://doi.org/10.1038/ng.2495

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2495

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer