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.

Acute Leukemias

EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia

Abstract

Overexpression of the ecotropic virus integration-1 (EVI1) gene (EVI1+), localized at chromosome 3q26, is associated with adverse outcome in adult acute myeloid leukemia (AML). In pediatric AML, 3q26 abnormalities are rare, and the role of EVI1 is unknown. We studied 228 pediatric AML samples for EVI1+ using gene expression profiling and RQ-PCR. EVI1+ was found in 20/213 (9%) of children with de novo AML, and in 4/8 with secondary AML. It was predominantly found in MLL-rearranged AML (13/47), monosomy 7 (2/3), or FAB M6/7 (6/10), and mutually exclusive with core-binding factor AML, t(15;17), and NPM1 mutations. Fluorescent in situ hybridization (FISH) was performed to detect cryptic 3q26 abnormalities. However, none of the EVI1+ patients harbored structural 3q26 alterations. Although significant differences in 4 years pEFS for EVI1+ and EVI1− pediatric AML were observed (28%±11 vs 44%±4, P=0.04), multivariate analysis did not identify EVI1+ as an independent prognostic factor. We conclude that EVI1+ can be found in 10% of pediatric AML. Although EVI1+ was not an independent prognostic factor, it was predominantly found in subtypes of pediatric AML that are related with an intermediate to unfavorable prognosis. Further research should explain the role of EVI1+ in disease biology in these cases. Remarkably, no 3q26 abnormalities were identified in EVI1+ pediatric AML.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  1. Wieser R . The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Gene 2007; 396: 346–357.

    CAS  Article  Google Scholar 

  2. Morishita K, Parganas E, William CL, Whittaker MH, Drabkin H, Oval J et al. Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300-400 kilobases on chromosome band 3q26. Proc Natl Acad Sci USA 1992; 89: 3937–3941.

    CAS  Article  Google Scholar 

  3. Matsugi T, Morishita K, Ihle JN . Identification, nuclear localization, and DNA-binding activity of the zinc finger protein encoded by the Evi-1 myeloid transforming gene. Mol Cell Biol 1990; 10: 1259–1264.

    CAS  Article  Google Scholar 

  4. Hoyt PR, Bartholomew C, Davis AJ, Yutzey K, Gamer LW, Potter SS et al. The Evi1 proto-oncogene is required at midgestation for neural, heart, and paraxial mesenchyme development. Mech Dev 1997; 65: 55–70.

    CAS  Article  Google Scholar 

  5. Morishita K, Parker DS, Mucenski ML, Jenkins NA, Copeland NG, Ihle JN . Retroviral activation of a novel gene encoding a zinc finger protein in IL-3-dependent myeloid leukemia cell lines. Cell 1988; 54: 831–840.

    CAS  Article  Google Scholar 

  6. Nucifora G, Laricchia-Robbio L, Senyuk V . EVI1 and hematopoietic disorders: history and perspectives. Gene 2006; 368: 1–11.

    CAS  Article  Google Scholar 

  7. Spensberger D, Delwel R . A novel interaction between the proto-oncogene Evi1 and histone methyltransferases, SUV39H1 and G9a. FEBS Lett 2008; 582: 2761–2767.

    CAS  Article  Google Scholar 

  8. Cattaneo F, Nucifora G . EVI1 recruits the histone methyltransferase SUV39H1 for transcription repression. J Cell Biochem 2008; 105: 344–352.

    CAS  Article  Google Scholar 

  9. Aytekin M, Vinatzer U, Musteanu M, Raynaud S, Wieser R . Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5′-ends. Gene 2005; 356: 160–168.

    CAS  Article  Google Scholar 

  10. Fears S, Mathieu C, Zeleznik-Le N, Huang S, Rowley JD, Nucifora G . Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family. Proc Natl Acad Sci USA 1996; 93: 1642–1647.

    CAS  Article  Google Scholar 

  11. Huang S, Shao G, Liu L . The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatin-mediated gene expression. J Biol Chem 1998; 273: 15933–15939.

    CAS  Article  Google Scholar 

  12. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S, Hack R et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 2003; 101: 837–845.

    Article  Google Scholar 

  13. Lugthart S, van Drunen E, van Norden Y, van Hoven A, Erpelinck CA, Valk PJ et al. High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood 2008; 111: 4329–4337.

    CAS  Article  Google Scholar 

  14. Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik MV, Steuber CP et al. Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. Blood 1999; 94: 3707–3716.

    CAS  PubMed  Google Scholar 

  15. Vardiman JW, Harris NL, Brunning RD . The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100: 2292–2302.

    CAS  Article  Google Scholar 

  16. Kardos G, Zwaan CM, Kaspers GJ, de-Graaf SS, de Bont ES, Postma A et al. Treatment strategy and results in children treated on three Dutch Childhood Oncology Group acute myeloid leukemia trials. Leukemia 2005; 19: 2063–2071.

    CAS  Article  Google Scholar 

  17. Gibson BE, Wheatley K, Hann IM, Stevens RF, Webb D, Hills RK et al. Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 2005; 19: 2130–2138.

    CAS  Article  Google Scholar 

  18. Creutzig U, Zimmermann M, Ritter J, Reinhardt D, Hermann J, Henze G et al. Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials. Leukemia 2005; 19: 2030–2042.

    CAS  Article  Google Scholar 

  19. Den Boer ML, Harms DO, Pieters R, Kazemier KM, Gobel U, Korholz D et al. Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia. J Clin Oncol 2003; 21: 3262–3268.

    CAS  Article  Google Scholar 

  20. Van Vlierberghe P, van Grotel M, Beverloo HB, Lee C, Helgason T, Buijs-Gladdines J et al. The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. Blood 2006; 108: 3520–3529.

    CAS  Article  Google Scholar 

  21. Balgobind BV, Van Vlierberghe P, van den Ouweland AM, Beverloo HB, Terlouw-Kromosoeto JN, van Wering ER et al. Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood 2008; 111: 4322–4328.

    CAS  Article  Google Scholar 

  22. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434–2439.

    CAS  Article  Google Scholar 

  23. Kiyoi H, Naoe T, Yokota S, Nakao M, Minami S, Kuriyama K et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia 1997; 11: 1447–1452.

    CAS  Article  Google Scholar 

  24. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, Meijer J, van Oosterhoud S, van Putten WL, Valk PJ et al. Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Hematol J 2003; 4: 31–40.

    Article  Google Scholar 

  25. Hollink IH, Zwaan CM, Zimmermann M, Arentsen-Peters TC, Pieters R, Cloos J et al. Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML. Leukemia 2009; 23: 262–270.

    CAS  Article  Google Scholar 

  26. Balgobind BV, Hollink IHIM, Reinhardt D, van Wering ER, de Graaf SSN, Baruchel A et al. Low frequency of MLL-PTD detected in pediatric acute myeloid leukemia using MLPA screening. ASH Annual Meet Abstr 2008; 112: 1512.

    Google Scholar 

  27. Irizarry RA, Gautier L, Bolstad BM, Miller C, Astrand M, Cope LM et al. Affy: methods for affymetrix oligonucleotide arrays. Part of Bioconducter, http://www.bioconducter.org.

  28. Huber W, von Heydebreck A, Sultmann H, Poustka A, Vingron M . Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics (Oxford, England) 2002; 18 (Suppl 1): S96–S104.

    Article  Google Scholar 

  29. Team RDC. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2007.

  30. Smyth G . Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 2004; 3: 1.

    Article  Google Scholar 

  31. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc B Met 1995; 57: 289–300.

    Google Scholar 

  32. Meijerink J, Mandigers C, van de Locht L, Tonnissen E, Goodsaid F, Raemaekers J . A novel method to compensate for different amplification efficiencies between patient DNA samples in quantitative real-time PCR. J Mol Diagn 2001; 3: 55–61.

    CAS  Article  Google Scholar 

  33. Lu Q, Wright DD, Kamps MP . Fusion with E2A converts the Pbx1 homeodomain protein into a constitutive transcriptional activator in human leukemias carrying the t(1;19) translocation. Mol Cell Biol 1994; 14: 3938–3948.

    CAS  Article  Google Scholar 

  34. Kuo YH, Zaidi SK, Gornostaeva S, Komori T, Stein GS, Castilla LH . Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice. Blood 2009; 113: 3323–3332.

    CAS  Article  Google Scholar 

  35. Laricchia-Robbio L, Nucifora G . Significant increase of self-renewal in hematopoietic cells after forced expression of EVI1. Blood Cells Mol Dis 2008; 40: 141–147.

    CAS  Article  Google Scholar 

  36. Kilbey A, Stephens V, Bartholomew C . Loss of cell cycle control by deregulation of cyclin-dependent kinase 2 kinase activity in Evi-1 transformed fibroblasts. Cell Growth Differ 1999; 10: 601–610.

    CAS  PubMed  Google Scholar 

  37. Hasle H, Alonzo TA, Auvrignon A, Behar C, Chang M, Creutzig U et al. Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: an international retrospective study. Blood 2007; 109: 4641–4647.

    CAS  Article  Google Scholar 

  38. Barnard DR, Alonzo TA, Gerbing RB, Lange B, Woods WG . Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: report from the Children's Oncology Group. Pediatr Blood Cancer 2007; 49: 17–22.

    Article  Google Scholar 

  39. Gilliland DG, Griffin JD . The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100: 1532–1542.

    CAS  Article  Google Scholar 

  40. Goemans BF, Zwaan CM, Miller M, Zimmermann M, Harlow A, Meshinchi S et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia 2005; 19: 1536–1542.

    CAS  Article  Google Scholar 

  41. Chen W, Kumar AR, Hudson WA, Li Q, Wu B, Staggs RA et al. Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells. Cancer Cell 2008; 13: 432–440.

    CAS  Article  Google Scholar 

  42. Tonnies H, Huber S, Kuhl JS, Gerlach A, Ebell W, Neitzel H . Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor. Blood 2003; 101: 3872–3874.

    CAS  Article  Google Scholar 

  43. Balgobind BV, Raimondi SC, Harbott J, Zimmermann M, Alonzo TA, Auvrignon A et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 2009; 114: 2489–2496.

    CAS  Article  Google Scholar 

  44. Laricchia-Robbio L, Fazzina R, Li D, Rinaldi CR, Sinha KK, Chakraborty S et al. Point mutations in two EVI1 Zn fingers abolish EVI1-GATA1 interaction and allow erythroid differentiation of murine bone marrow cells. Mol Cell Biol 2006; 26: 7658–7666.

    CAS  Article  Google Scholar 

  45. Kreider BL, Orkin SH, Ihle JN . Loss of erythropoietin responsiveness in erythroid progenitors due to expression of the Evi-1 myeloid-transforming gene. Proc Natl Acad Sci USA 1993; 90: 6454–6458.

    CAS  Article  Google Scholar 

  46. Shimizu S, Nagasawa T, Katoh O, Komatsu N, Yokota J, Morishita K . EVI1 is expressed in megakaryocyte cell lineage and enforced expression of EVI1 in UT-7/GM cells induces megakaryocyte differentiation. Biochem Biophys Res Commun 2002; 292: 609–616.

    CAS  Article  Google Scholar 

  47. Louz D, van den Broek M, Verbakel S, Vankan Y, van Lom K, Joosten M et al. Erythroid defects and increased retrovirally-induced tumor formation in Evi1 transgenic mice. Leukemia 2000; 14: 1876–1884.

    CAS  Article  Google Scholar 

  48. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004; 350: 1617–1628.

    CAS  Article  Google Scholar 

  49. Lugthart S, Figueroa ME, Valk PJM, Li Y, Erpelinck-Verschueren C, Greally J et al. Two different EVI1 expressing poor-risk AML subgroups with Distinct epigenetic signatures uncovered by genome wide DNA methylation profiling. ASH Annual Meet Abstr 2008; 112: 757.

    Google Scholar 

  50. Shimabe M, Goyama S, Watanabe-Okochi N, Yoshimi A, Ichikawa M, Imai Y et al. Pbx1 is a downstream target of Evi-1 in hematopoietic stem/progenitors and leukemic cells. Oncogene 2009; 28: 4364–4374.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was funded by the NWO ‘Netherlands Organization for Scientific Research’ (BVB), KOCR ‘Kinder-Oncologisch Centrum Rotterdam’ (BVB and IHH) and EHA (SL).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M M van den Heuvel-Eibrink.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Author contribution

BVB designed and performed research and wrote the paper. SL and RD designed research. IHH designed and performed research. HBB performed FISH analysis. EW, SSNG, GJK, DR, UC, JS, and JT made this research possible by collecting patient samples and characteristics in their own study groups and providing additional information. MMH-E, CMZ, and RP designed and supervised research and wrote the paper.

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Balgobind, B., Lugthart, S., Hollink, I. et al. EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia. Leukemia 24, 942–949 (2010). https://doi.org/10.1038/leu.2010.47

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.47

Keywords

  • EVI1 expression
  • pediatric AML
  • MDS1/EVI1 expression

Further reading

Search

Quick links