Monitoring of acute leukemia patients during and after treatment for the presence of remaining leukemic cells (minimal residual disease, MRD) has been shown to give major insight into the effectiveness of treatment. However, so far the applicability of this strategy has been limited to those leukemia subsets characterized by genetic markers amenable to sensitive detection by PCR. Although PCR for immunoglobulin and T cell receptor gene rearrangement represents the gold standard for MRD detection in most cases of ALL without any fusion gene transcripts as molecular markers available, the situation in AML is more complicated because, at present, more than 50% of them lack any sort of clonality markers suitable for MRD monitoring. Thus, a number of studies have been performed in an attempt to identify cytogenetic and molecular abnormalities associated with leukemic transformation. In this paper we describe the effectiveness of the quantitative assessment of the Wilms tumor gene (WT1) transcript as a molecular marker for the detection of the leukemic clone useful for monitoring the presence of MRD in all the patients affected by acute and chronic leukemias as well as myelodysplastic syndromes.

1.
Fearon ER, Volgelstein B, Feinberg AP: Somatic deletion and duplication of genes on chromosome 11 in Wilms’ tumours. Nature 1984;309:176–178.
2.
Koufos A, Hansen MF, Lampkin BC, Workman ML, Copeland NG, Jenkins NA, Cavenee WK: Loss of alleles on human chromosome 11 during genesis of Wilms’ tumor. Nature 1984;309:170–172.
3.
Miller RW, Fraumeni JF, Manning MD: Association of Wilms’ tumor with aniridia, hemihypertrophy and other congenital anomalies. N Engl J Med 1964;270:922–927.
4.
Call KM, Glaser T, Ito CY, Buckler A, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 1990;60:509–520.
5.
Cook DM, Hinkes MT, Bernfield M, Rauscher FJ 3rd: Transcriptional activation of the syndecan-1 promoter by the Wilms’ tumor protein WT1. Oncogene 1996;13:1789–1799.
6.
Englert C, Hou X, Maheswaran S, Bennett P, Ngwu C, Re GG, Garvin AJ, Rosner MR, Haber DA: WT1 suppress synthesis of the epidermal growth factor receptor and induces apoptosis. EMBO J 1995;14:4662–4675.
7.
Hewitt SM, Hamada S, McDonnell TJ Rauscher FJ 3rd, Saunders GF: Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms’ tumor suppressor gene WT1. Cancer Res 1995;55:5386–5389.
8.
Hosono S, Gross I, English MA, Haira KM, Fearon ER, Licht JD: E-cadherin is a WT1 target gene. J Biol Chem 2000;275:10943–10953.
9.
Lee SB, Huang K, Palmer R, Troung VB, Herzlinger D, Kolquist KA, Wong J, Paulding C, Yoon SK, Gerald W, Oliner JD, Haber DA: The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin. Cell 1999;98:663–673.
10.
Park S, Schalling M, Bernard A, Maheswaran S, Shipley GC, Roberts D, Fletcher J, Schpman R, Rheinwald J, Demetri G: The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma. Nat Genet 1993;4:415–420.
11.
Little M, Holmes G, Walsh P: WT1:What has the last decade told us? Bioessay 1999;21:191–202.
12.
Pritchard-Jones K, Fleming S: Cell types expressing the Wilms’ tumour gene (WT1) in Wilms’ tumour: Implications for tumour histogenesis. Oncogene 1991;6:2211–2220.
13.
Baird PM, Simmons PJ: Expression of the Wilms tumor gene (WT1) in normal hemopoiesis. Exp Hematol 1997;25:312–320.
14.
Maurer U, Brieger J, Weidmann E, Mitrou PS, Hoelzer D, Bergmann L: The Wilms’ tumor gene is expressed in a subset of CD34+ progenitors and downregulated early in the course of differentiation in vitro. Exp Hematol 1997;25:945–950.
15.
Menssen HD, Renkl HJ, Entezami M, Thiel E: Wilms’ tumor gene expression in human CD34+ hematopoietic progenitors during fetal development and early clonogenic growth. Blood 1997;89:3486–3487.
16.
Sekiya M, Adachi M, Hinoda Y, Imai K, Yachi A: Downregulation of the Wilms’ tumor gene (wt1) during myelomonocytic differentiation in HL60 cells. Blood 1994;83:1876–1882.
17.
Menssen HD, Renkl HJ, Rodeck U, Maurer J, Nutter M, Schwartz S, Reinhardt R, Thiel E: Presence of Wilms’ tumor gene (WT1) transcripts and WT1 nuclear protein in the majority of human acute leukemias. Leukemia 1995;9:1060–1067.
18.
Miwa H, Beran M, Saunders GF: Expression of the Wilms’ tumor gene (WT1) in human leukemias. Leukemia 1992;6:405–409.
19.
Algar EM, Khromykh T, Smith SI, Blackburn DM, Bryson GJ, Smith PJ: A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukemia cell lines. Oncogene 1996;12:1005–1014.
20.
Deuel TF, Guan LS, Wang ZY: Wilms’ tumor gene product WT1 arrests macrophage differentiation of HL60 cells through its zinc-finger domain. Biochem Biophys Res Commun 1999;254:192–196.
21.
Inoue K, Ogawa H, Sonoda Y, Kimura T, Sakabe H, Oka Y, Miyake S, Tamaki H, Oji Y, Yamagami T, Tatekawa T, Soma T, Kishimoto T, Sugiyama H: Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 1997;89:1405–1412.
22.
Smith SI, Weil D, Johnson GR, Boyd AW, Li CL: Expression of the Wilms’ tumor suppressor gene, WT1 is upregulated by leukemia inhibitory factor and induces monocytic differentiation in M1 leukemic cells. Blood 1998;91:764–773.
23.
Svedberg H, Chylicki K, Baldetorp B, Rauscher FL 3rd, Gullberg U: Constitutive expression of the Wilms’ tumor gene (WT1) in the leukemic cell line U937 blocks part of the differentiation program. Oncogene 1998;16:925–932.
24.
Ellisen LW, Carlesso N, Cheng T, Scadden DT, Haber DA: The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitors cells. EMBO J 2001;20:1897–1909.
25.
Cilloni D, Gottardi E, De Micheli D, Serra A, Volpe G, Messa F, Rege-Cambrin G, Guerrasio A, Divona M, Lo Coco F, Saglio G: Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 2002;16:2115–2121.
26.
Gaiger A, Schmid D, Heinze G, Linnerth B, Greinix H, Halhs P, Tisljar K, Prigljnger S, Mitterbauer M, Novak M, Mitterbauer G, Mannhalter C, Haas OA, Lechner K, Jäger U: Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia. Leukemia 1998;12:1886–1894.
27.
Inoue K, Tamaki H, Ogawa H, Oka Y, Soma T, Tatekawa T, Oji Y, Tsuboi A, Kim EH, Kawakami M, Akiyama T, Kischimoto T, Sugiyama H: Wilms’ tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells. Blood 1998;91:2969–2976.
28.
Maurer U, Weidmann E, Karakas T, Hoelzer D, Bergmann L: Wilms tumor gene (wt1) mRNA is equally expressed in blast cells from acute myeloid leukemia and normal CD34+ progenitors. Blood 1997;90:4230–4232.
29.
Menssen HD, Siehl JM, Thiel E: Wilms tumor gene (WT1) expression as a panleukemic marker. Int J Hematol 2002;76:103–109.
30.
Trka J, Kalinova M, Hrusak O, Zuna J, Krejci O, Madzo J, Sedlacek P, Vavra V, Michalova K, Jarosova M, Stary J: Real time quantitative PCR detection of WT1 gene expression in children with AML: Prognostic significance, correlation with disease status and residual disease detection by flow cytometry. Leukemia 2002;16:1381–1389.
31.
Cilloni D, Messa F, Gottardi E, Fava M, Scaravaglio P, Bertini M, Girotto M, Marinone C, Ferrero D, Gallamini A, Levis A, Saglio G: Very significant correlation between WT1 expression level and the IPSS score in patients with myelodysplastic syndromes. J Clin Oncol 2003;21:1988–1995.
32.
Kreuzer KA, Saborowski A, Lupberger J, Appelt C, Na IK, Le Coutre P, Schmidt CA: Fluorescent 5′-exonuclease assay for the absolute quantification of Wilms’ tumour gene (WT1) mRNA: Implications for monitoring human leukemias. Br J Haematol 2001;114:313–318.
33.
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: The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia 1999;13:393–399.
34.
Schmid D, Heinze G, Linnerth B: Prognostic significance of WT1 gene expression at diagnosis in adult de novo acute myeloid leukemia. Leukemia 1997;11:639–643.
35.
Inoue K, Ogawa H, Yamagami T, Soma T, Tani Y, Tatekawa T, Oji Y, Tamaki H, Kyo T, Dohy H, Hiraoka A, Masaoka T, Koshimoto T, Sugiyama H: Log-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. Blood 1996;88:2267–2278.
36.
Ogawa H, Tamaki H, Ikegame K Soma T, Kawakami M, Tsuboi A, Kim EH, Hosen N, Murakami H, Fujioka T, Masuda T, Taniguchi Y, Nischida S, Oji Y, Oka J, Sugiyama H: The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood 2003;101:1698–1704.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.