Abstract
Expression of the gene Wilms tumor 1 (WT1) has been suggested as a marker of minimal residual disease in acute myeloid leukemia (AML), but literature data are not without controversy. Our aim was to assess the presence, magnitude and temporal changes of WT1 expression as prognostic factors. 60 AML patients were followed until death or the end of the 6-year observation period. Blood samples were taken at diagnosis, post-induction, during remission and in case of a relapse. Using quantitative real-time PCR, we determined WT1 expression from each sample, normalized it against the endogenous control gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and classified samples as negative, moderately positive or highly positive. We divided the patients into groups based on detected WT1 expression values, illustrated overall and disease-free survival on Kaplan-Meier curves, and compared differences between each group by the logrank test. Disappearance of WT1-positivity during chemotherapy had a favorable effect on survival. Interestingly, no difference was seen between the survivals of WT1-positive subgroups that expressed moderate or high levels of WT1 mRNA. A 1-log decrease in WT1 expression without becoming negative did not affect prognosis, either. Our results suggest that defining a cut-off value for WT1-positivity, rather than just using logarithmic figures of changes in gene expression, might have prognostic use in post-induction AML patients. We encourage further, larger-scale studies.
Similar content being viewed by others
References
Rose EA, Glaser T, Jones C, Smith CL, Lewis WH, Call KM, Minden M, Champagne E, Bonetta L, Yeger H, Housman DE (1990) Complete physical map of the WAGR region of 11p13 localizes a candidate Wilms' tumor gene. Cell 60:495–508
Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (1990) Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60:509–520
Essafi A, Webb A, Berry RL, Slight J, Burn SF, Spraggon L, Velecela V, Martinez-Estrada OM, Wiltshire JH, Roberts SG, Brownstein D, Davies JA, Hastie ND, Hohenstein P (2011) A wt1-controlled chromatin switching mechanism underpins tissue-specific wnt4 activation and repression. Dev Cell 21:559–574
Morrison AA, Viney RL, Ladomery MR (2008) The post-transcriptional roles of WT1, a multifunctional zinc-finger protein. Biochim Biophys Acta 1785:55–62
Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE (1991) Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci U S A 88:9618–9622
Miller-Hodges E, Hohenstein P (2012) WT1 in disease: shifting the epithelial-mesenchymal balance. J Pathol 226:229–240
Miwa H, Beran M, Aunders GF (1992) Expression of the Wilms tumor gene (WT1) in human leukemias. Leukemia 6:405–409
Vidovic K, Svensson E, Nilsson B, Thuresson B, Olofsson T, Lennartsson A, Gullberg U (2010) Wilms' tumor gene 1 protein represses the expression of the tumor suppressor interferon regulatory factor 8 in human hematopoietic progenitors and in leukemic cells. Leukemia 24:992–1000
Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E, Hoelzer D (1997) High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 90:1217–1225
Gaiger A, Schmid D, Heinze G, Linnerth B, Greinix H, Kalhs P, Tisljar K, Priglinger S, Laczika K, Mitterbauer M, Novak M, Mitterbauer G, Mannhalter C, Haas OA, Lechner K, Jäger U (1998) Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia. Leukemia 12:1886–1894
Noronha SA, Farrar JE, Alonzo TA, Gerbing RB, Lacayo NJ, Dahl GV, Ravindranath Y, Arceci RJ, Loeb DM (2009) WT1 expression at diagnosis does not predict survival in pediatric AML: a report from the children's oncology group. Pediatr Blood Cancer 53:1136–1139
Mossallam GI, Hamid TM, Mahmoud HK (2013) Prognostic significance of WT1 expression at diagnosis and end of induction in Egyptian adult acute myeloid leukemia patients. Hematology 18:69–73
Gray JX, McMillen L, Mollee P, Paul S, Lane S, Bird R, Gill D, Saal R, Marlton P (2012) WT1 expression as a marker of minimal residual disease predicts outcome in acute myeloid leukemia when measured post-consolidation. Leuk Res 36:453–458
Andersson C, Li X, Lorenz F, Golovleva I, Wahlin A, Li A (2012) Reduction in WT1 gene expression during early treatment predicts the outcome in patients with acute myeloid leukemia. Diagn Mol Pathol 21:225–233
Polak J, Hajkova H, Haskovec C, Cechova H, Marinov I, Mikulenkova D, Markova J, Markova M, Vitek A, Valkova V (2013) Quantitative monitoring of WT1 expression in peripheral blood before and after allogeneic stem cell transplantation for acute myeloid leukemia - a useful tool for early detection of minimal residual disease. Neoplasma 60:74–82
Cilloni D, Messa F, Arruga F, Defilippi I, Gottardi E, Fava M, Carturan S, Catalano R, Bracco E, Messa E, Nicoli P, Diverio D, Sanz MA, Martinelli G, Lo-Coco F, Saglio G (2008) Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapy. Haematologica 93:921–924
Cilloni D, Renneville A, Hermitte F, Hills RK, Daly S, Jovanovic JV, Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van der Heijden A, van der Reijden BA, Jansen JH, van der Velden VH, Ommen H, Preudhomme C, Saglio G, Grimwade D (2009) Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol 27:5195–5201
Cilloni D, Saglio G (2004) WT1 as a universal marker for minimal residual disease detection and quantification in myeloid leukemias and in myelodysplastic syndrome. Acta Haematol 112:79–84
Ogawa H, Ikegame K, Kawakami M, Tamaki H (2004) WT1 gene transcript assay for relapse in acute leukemia after transplantation. Leuk Lymphoma 45:1747–1753
Gianfaldoni G, Mannelli F, Ponziani V, Longo G, Bencini S, Bosi A, Vannucchi AM (2010) Early reduction of WT1 transcripts during induction chemotherapy predicts for longer disease free and overall survival in acute myeloid leukemia. Haematologica 95:833–836
Sugiyama H (2010) WT1 (Wilms' Tumor gene 1): biology and cancer immunotherapy. Jpn J Clin Oncol 40:377–387
Renneville A, Boissel N, Zurawski V, Llopis L, Biggio V, Nibourel O, Philippe N, Thomas X, Dombret H, Preudhomme C (2009) Wilms tumor 1 gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the acute leukemia French association. Cancer 115:3719–3727
Hou HA, Huang TC, Lin LI, Liu CY, Chen CY, Chou WC, Tang JL, Tseng MH, Huang CF, Chiang YC, Lee FY, Liu MC, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Tien HF (2010) WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. Blood 115:5222–5231
Huff V (2011) Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene. Nat Rev Cancer 11:111–121
Acknowledgments
This work was supported by the Social Renewal Operational Programme of Hungary. The authors do not have a financial relationship with the sponsors of the research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Zsófia Ujj and Gergely Buglyó contributed equally to this work.
Rights and permissions
About this article
Cite this article
Ujj, Z., Buglyó, G., Udvardy, M. et al. WT1 Expression in Adult Acute Myeloid Leukemia: Assessing its Presence, Magnitude and Temporal Changes as Prognostic Factors. Pathol. Oncol. Res. 22, 217–221 (2016). https://doi.org/10.1007/s12253-015-0002-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12253-015-0002-0