Skip to main content

Advertisement

SpringerLink
Log in

Simultaneous analysis of the expression of 14 genes with individual prognostic value in myelodysplastic syndrome patients at diagnosis: WT1 detection in peripheral blood adversely affects survival

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Several studies have evaluated the prognostic value of the individual expression of certain genes in patients with myelodysplastic syndromes (MDS). However, none of them includes their simultaneous analysis by quantitative polymerase chain reaction (PCR). We evaluated relative expression levels of 14 molecular markers in 193 peripheral blood samples from untreated MDS patients using real-time PCR. Detectable WT1 expression levels, low TET2, and low IER3 gene expression were the only markers showing in univariate analysis a poor prognostic value for all treatment-free (TFS), progression-free (PFS), and overall survival (OS). In multivariate analysis, molecular parameters associated with a shorter TFS were: WT1 detection (p = 0.014), low TET2 (p = 0.002), and low IER3 expression (p = 0.025). WT1 detection (p = 0.006) and low TET2 (p = 0.006) expression were associated with a shorter PFS when multivariate analysis was carried out by including only molecular markers. Molecular values with an independent value in OS were: WT1 detection (p = 0.003), high EVI1 expression (p = 0.001), and undetectatable p15-CDKN2B (p = 0.037). WT1 expressers were associated with adverse clinical–biological features, high IPSS and WPSS scoring, and unfavorable molecular expression profile. In summary, detectable WT1 expression levels, and low TET2 and low IER3 expression in peripheral blood showed a strong association with adverse prognosis in MDS patients at diagnosis. However, WT1 was the only molecular marker displaying an independent prognostic value in both OS and TFS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Tefferi A, Vardiman JW (2009) Myelodysplastic syndromes. N Engl J Med 361:1872–1885

    Article  PubMed  CAS  Google Scholar 

  2. Cazzola M, Malcovati L (2005) Myelodysplastic syndromes—coping with ineffective hematopoiesis. N Engl J Med 352:536–538

    Article  PubMed  CAS  Google Scholar 

  3. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103:620–625

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114:937–951

    Article  PubMed  CAS  Google Scholar 

  6. Cazzola M, Malcovati L (2010) Prognostic classification and risk assessment in myelodysplastic syndromes. Hematol Oncol Clin N Am 24:459–468

    Article  Google Scholar 

  7. Nimer SD (2008) Myelodysplastic syndromes. Blood 111:4841–4851

    Article  PubMed  CAS  Google Scholar 

  8. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088

    PubMed  CAS  Google Scholar 

  9. Malcovati L, Germing U, Kuendgen A, la Porta MG, Pascutto C, Invernizzi R, Giagounidis A, Hildebrandt B, Bernasconi P, Knipp S, Strupp C, Lazzarino M, Aul C, Cazzola M (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25:3503–3510

    Article  PubMed  Google Scholar 

  10. Bowen DT, Fenaux P, Hellstrom-Lindberg E, de Witte T (2008) Time-dependent prognostic scoring system for myelodysplastic syndromes has significant limitations that may influence its reproducibility and practical application. J Clin Oncol 26:1180–1182

    Article  PubMed  Google Scholar 

  11. Nowell PC (1992) Chromosome abnormalities in myelodysplastic syndromes. Semin Oncol 19:25–33

    PubMed  CAS  Google Scholar 

  12. Bejar R, Stevenson K, Bdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, Ebert BL (2011) Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 364:2496–2506

    Article  PubMed  CAS  Google Scholar 

  13. Delhommeau F, Dupont S, Della VV, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lecluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguie F, Fontenay M, Vainchenker W, Bernard OA (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301

    Article  PubMed  Google Scholar 

  14. Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B, Hunault-Berger M, Slama B, Vey N, Lacombe C, Solary E, Birnbaum D, Bernard OA, Fontenay M (2010) Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 24:1094–1096

    Article  PubMed  CAS  Google Scholar 

  15. Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann M, Gohring G, Schumann C, Bug G, Ottmann O, Hofmann WK, Schlegelberger B, Ganser A, Heuser M (2010) IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica 95:1668–1674

    Article  PubMed  CAS  Google Scholar 

  16. Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M, Tadrist Z, Olschwang S, Vey N, Birbaum D, Gelsi-Boyer V, Mozziconacci MJ (2010) Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer 10:401

    Article  PubMed  Google Scholar 

  17. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41:838–842

    Article  PubMed  CAS  Google Scholar 

  18. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL (2009) Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:144–147

    Article  PubMed  CAS  Google Scholar 

  19. Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, La-Valle V, Picard F, Viguie F, Quesnel B, Beyne-Rauzy O, Solary E, Vey N, Hunault-Berger M, Fenaux P, Mansat-De Mas V, Delabesse E, Guardiola P, Lacombe C, Vainchenker W, Preudhomme C, Dreyfus F, Bernard OA, Birnbaum D, Fontenay M (2009) TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood 114:3285–3291

    Article  PubMed  CAS  Google Scholar 

  20. Hofmann WK, de Vos S, Komor M, Hoelzer D, Wachsman W, Koeffler HP (2002) Characterization of gene expression of CD34+ cells from normal and myelodysplastic bone marrow. Blood 100:3553–3560

    Article  PubMed  CAS  Google Scholar 

  21. Mills KI, Kohlmann A, Williams PM, Wieczorek L, Liu WM, Li R, Wei W, Bowen DT, Loeffler H, Hernandez JM, Hofmann WK, Haferlach T (2009) Microarray-based classifiers and prognosis models identify subgroups with distinct clinical outcomes and high risk of AML transformation of myelodysplastic syndrome. Blood 114:1063–1072

    Article  PubMed  CAS  Google Scholar 

  22. Sridhar K, Ross DT, Tibshirani R, Butte AJ, Greenberg PL (2009) Relationship of differential gene expression profiles in CD34+ myelodysplastic syndrome marrow cells to disease subtype and progression. Blood 114:4847–4858

    Article  PubMed  CAS  Google Scholar 

  23. Wang YY, Cen JN, He J, Shen HJ, Liu DD, Yao L, Qi XF, Chen ZX (2009) Accelerated cellular senescence in myelodysplastic syndrome. Exp Hematol 37:1310–1317

    Article  PubMed  CAS  Google Scholar 

  24. Pellagatti A, Cazzola M, Giagounidis AA, Malcovati L, Porta MG, Killick S, Campbell LJ, Wang L, Langford CF, Fidler C, Oscier D, Aul C, Wainscoat JS, Boultwood J (2006) Gene expression profiles of CD34+ cells in myelodysplastic syndromes: involvement of interferon-stimulated genes and correlation to FAB subtype and karyotype. Blood 108:337–345

    Article  PubMed  CAS  Google Scholar 

  25. Pellagatti A, Marafioti T, Paterson JC, Malcovati L, la Porta MG, Jadersten M, Pushkaran B, George TI, Arber DA, Killick S, Giagounidis A, Hellstrom-Lindberg E, Cazzola M, Wainscoat JS, Boultwood J (2009) Marked downregulation of the granulopoiesis regulator LEF1 is associated with disease progression in the myelodysplastic syndromes. Br J Haematol 146:86–90

    Article  PubMed  Google Scholar 

  26. Santamaria CM, Chillon MC, Garcia-Sanz R, Perez C, Caballero MD, Ramos F, de Coca AG, Alonso JM, Giraldo P, Bernal T, Queizan JA, Rodriguez JN, Fernandez-Abellan P, Barez A, Penarrubia MJ, Balanzategui A, Vidriales MB, Sarasquete ME, Alcoceba M, Az-Mediavilla J, San Miguel JF, Gonzalez M (2009) Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia. Blood 114:148–152

    Article  PubMed  CAS  Google Scholar 

  27. Briatore F, Barrera G, Pizzimenti S, Toaldo C, Casa CD, Laurora S, Pettazzoni P, Dianzani MU, Ferrero D (2009) Increase of telomerase activity and hTERT expression in myelodysplastic syndromes. Cancer Biol Ther 8:883–889

    PubMed  CAS  Google Scholar 

  28. Cilloni D, Gottardi E, Messa F, Fava M, Scaravaglio P, Bertini M, Girotto M, Marinone C, Ferrero D, Gallamini A, Levis A, Saglio G (2003) Significant correlation between the degree of WT1 expression and the International Prognostic Scoring System Score in patients with myelodysplastic syndromes. J Clin Oncol 21:1988–1995

    Article  PubMed  CAS  Google Scholar 

  29. Prall WC, Czibere A, Grall F, Spentzos D, Steidl U, Giagounidis AA, Kuendgen A, Otu H, Rong A, Libermann TA, Germing U, Gattermann N, Haas R, Aivado M (2009) Differential gene expression of bone marrow-derived CD34+ cells is associated with survival of patients suffering from myelodysplastic syndrome. Int J Hematol 89:173–187

    Article  PubMed  CAS  Google Scholar 

  30. Steensma DP, Neiger JD, Porcher JC, Keats JJ, Bergsagel PL, Dennis TR, Knudson RA, Jenkins RB, Santana-Davila R, Kumar R, Ketterling RP (2009) Rearrangements and amplification of IER3 (IEX-1) represent a novel and recurrent molecular abnormality in myelodysplastic syndromes. Cancer Res 69:7518–7523

    Article  PubMed  CAS  Google Scholar 

  31. Metzeler KH, Maharry K, Radmacher MD, Mrozek K, Margeson D, Becker H, Curfman J, Holland KB, Schwind S, Whitman SP, Wu YZ, Blum W, Powell BL, Carter TH, Wetzler M, Moore JO, Kolitz JE, Baer MR, Carroll AJ, Larson RA, Caligiuri MA, Marcucci G, Bloomfield CD (2011) TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 29:1373–1381

    Article  PubMed  Google Scholar 

  32. Chou WC, Chou SC, Liu CY, Chen CY, Hou HA, Kuo YY, Lee MC, Ko BS, Tang JL, Yao M, Tsay W, Wu SJ, Huang SY, Hsu SC, Chen YC, Chang YC, Kuo YY, Kuo KT, Lee FY, Liu MC, Liu CW, Tseng MH, Huang CF, Tien HF (2011) TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 118:3803–3810

    Article  PubMed  CAS  Google Scholar 

  33. Albano F, Anelli L, Zagaria A, Coccaro N, Minervini A, Rossi AR, Specchia G (2011) Decreased TET2 gene expression during chronic myeloid leukemia progression. Leuk Res 35:e220-e222

    Google Scholar 

  34. Haber DA, Buckler AJ, Glaser T, Call KM, Pelletier J, Sohn RL, Douglass EC, Housman DE (1990) An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms’ tumor. Cell 61:1257–1269

    Article  PubMed  CAS  Google Scholar 

  35. Saglio G, Carturan S, Grillo S, Capella S, Arruga F, Defilippi I, Rosso V, Rauco M, Marina LA, Cilloni D (2005) WT1 overexpression: a clinically useful marker in acute and chronic myeloid leukemias. Hematology 10(Suppl 1):76–78

    Article  PubMed  Google Scholar 

  36. Barragán E, Cervera J, Bolufer P, Ballester S, Martin G, Fernandez P, Collado R, Sayas MJ, Sanz MA (2004) Prognostic implications of Wilms’ tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica 89:926–933

    PubMed  Google Scholar 

  37. Lange T, Hubmann M, Burkhardt R, Franke GN, Cross M, Scholz M, Leiblein S, Al-Ali HK, Edelmann J, Thiery J, Niederwieser D (2011) Monitoring of WT1 expression in PB and CD34(+) donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning. Leukemia 25:498–505

    Article  PubMed  CAS  Google Scholar 

  38. Miyawaki S, Hatsumi N, Tamaki T, Naoe T, Ozawa K, Kitamura K, Karasuno T, Mitani K, Kodera Y, Yamagami T, Koga D (2010) Prognostic potential of detection of WT1 mRNA level in peripheral blood in adult acute myeloid leukemia. Leuk Lymphoma 51:1855–1861

    Article  PubMed  CAS  Google Scholar 

  39. Tamaki H, Ogawa H, Ohyashiki K, Ohyashiki JH, Iwama H, Inoue K, Soma T, Oka Y, Tatekawa T, Oji Y, Tsuboi A, Kim EH, Kawakami M, Fuchigami K, Tomonaga M, Toyama K, Aozasa K, Kishimoto T, Sugiyama H (1999) The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia 13:393–399

    Article  PubMed  CAS  Google Scholar 

  40. Tamura H, Dan K, Yokose N, Iwakiri R, Ohta M, Sakamaki H, Tohyama K, Kondo A, Hyodo H, Nakamura K, Yamashita T, Elisseeva OA, Oka Y, Oji Y, Sugiyama H, Ogata K (2010) Prognostic significance of WT1 mRNA and anti-WT1 antibody levels in peripheral blood in patients with myelodysplastic syndromes. Leuk Res 34:986–990

    Article  PubMed  CAS  Google Scholar 

  41. Lugthart S, Drunen EV, Norden YV, Hoven AV, Erpelinck CA, Valk PJ, Beverloo HB, Lowenberg B, Delwel R (2008) High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood 111:4329–4337

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The Spanish MDS Group (GESMD), provided samples and clinical information from patients participating in the INBIOMED HEMA-001/2006 project (sponsored by Celgene S.L., Madrid). This work has been partially supported by the grants PI061351 and 00/0023-00 from the Spanish “Fondo de Investigaciones Sanitarias de la Seguridad Social”, 89/A/06 from the “Gerencia Regional de Salud, Junta Castilla y León”, and CIC, IBMCC (USAL-CSIC), Spain.

Conflicts of interest

All the authors have no conflict of interest to report.

Author information

Authors and Affiliations

  1. Servicio de Hematología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, Salamanca, 37007, Spain

    Carlos Santamaría, Noemi Puig, Consuelo del Cañizo, María Diez-Campelo, Montserrat Hernández, Carmen Chillón, Ramón García-Sanz, Jesús F. San Miguel & Marcos González

  2. Servicio de Hematología, Hospital de León, León, Spain

    Fernando Ramos & Javier Sánchez del Real

  3. Laboratorio de Biología Molecular, Hospital Universitario La Fe, Valencia, Spain

    Eva Barragán

  4. Servicio de Hematología, H. Universitario La Paz, Madrid, Spain

    Raquel de Paz

  5. Servicio de Hematología, Hospital del Mar, Barcelona, Spain

    Carme Pedro

  6. Servicio de Hematología, Hospital Universitario Marqués de Valdecilla, Santander, Spain

    Andrés Insunza

  7. Servicio de Hematología y Oncología, Hospital Clínico Universitario, Valencia, Spain

    Mar Tormo

  8. Servicio de Hematología, Hospital Universitario Germans Trias i Pujol, Badalona, Spain

    Blanca Xicoy

  9. Servicio de Hematología, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain

    Eduardo Salido

  10. Servicio de Hematología, Hospital Universitario La Fe, Valencia, Spain

    Guillermo F. Sanz

  11. Instituto de Biomedicina (IBIOMED), Universidad de León, León, Spain

    Fernando Ramos

  12. Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain

    Carlos Santamaría, Consuelo del Cañizo, Ramón García-Sanz, Jesús F. San Miguel & Marcos González

Authors
  1. Carlos Santamaría
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fernando Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noemi Puig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eva Barragán
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Raquel de Paz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carme Pedro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andrés Insunza
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mar Tormo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Consuelo del Cañizo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. María Diez-Campelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Blanca Xicoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eduardo Salido
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Javier Sánchez del Real
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Montserrat Hernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Carmen Chillón
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Guillermo F. Sanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Ramón García-Sanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jesús F. San Miguel
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Marcos González
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos Santamaría.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

Clinical and biological characteristics of MDS patients at diagnosis according to WT1 expression levels (DOC 46 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Santamaría, C., Ramos, F., Puig, N. et al. Simultaneous analysis of the expression of 14 genes with individual prognostic value in myelodysplastic syndrome patients at diagnosis: WT1 detection in peripheral blood adversely affects survival. Ann Hematol 91, 1887–1895 (2012). https://doi.org/10.1007/s00277-012-1538-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-012-1538-7

Keywords

Search

Navigation