WT1 as a Biomarker in Myelodysplastic Neoplasms: Clinical Correlations and Preliminary Data from an Iranian Cohort
-
Forouzan Bahmani
,
Farhad Zaker
,
Bahram Chahardouli
,
Majid Safa
,
Nasrin Alizadghandforoush
,
Saeed Mohammadi
,
Mohsen Nikbakht
,
Shahrbano Rostami
,
Ghasem Janbabaei
Abstract
Background: Although Wilms’ tumor 1 (WT1) mRNA overexpression is frequently observed in myelodysplastic neoplasms (MDS), its clinical and molecular significance remains incompletely defined across diverse populations; this study is the first to evaluate WT1 expression in Iranian patients with MDS.
Materials and Methods: WT1 expression was assessed in 58 MDS patients using an ELN-certified quantitative RT-PCR assay. Associations with clinical subtype, hematologic features, cytogenetic profiles, and molecular mutations were analyzed. Survival outcomes were evaluated using Kaplan–Meier and Cox regression analyses.
Results: WT1 overexpression was detected in 79.3% of patients and was significantly associated with advanced subtypes (MDS-EB1/EB2) and higher IPSS-R risk groups. Elevated WT1 levels correlated with an increased bone marrow (BM) blast percentage (P < 0.01). Although cytogenetic abnormalities were more frequent in patients with WT1 overexpression, the association did not reach statistical significance. No significant correlations were observed with peripheral blood (PB) cytopenias or mutations in RNA splicing genes. Importantly, WT1 overexpression was associated with shorter overall survival (OS) and progression-free survival (PFS). However, in multivariate analysis, ≥10% BM blasts and an abnormal karyotype remained independent predictors of poor outcome, whereas WT1 overexpression itself was not independently prognostic.
Conclusion: WT1 overexpression in MDS is associated with advanced disease features and poorer survival, though it is not an independent prognostic value. Its measurement may complement existing risk stratification, particularly in resource-limited settings.
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2. Oji Y, Nakamori S, Fujikawa M, et al. Overexpression of the Wilms' tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci. 2004;95(7):583-7.
3. Rampal R, Figueroa ME. Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia. Haematologica. 2016;101(6):672-9.
4. Rautenberg C, Germing U, Pechtel S, et al. Prognostic impact of peripheral blood WT1-mRNA expression in patients with MDS. Blood Cancer J. 2019;9(11):86.
5. Cilloni D, Renneville A, Hermitte F, et al. 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. 2009;27(31):5195-201.
6. Bergmann L, Miething C, Maurer U, et al. High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood. 1997;90(3):1217-25.
7. Hou HA, Huang TC, Lin LI, et al. 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. 2010;115(25):5222-31.
8. Nagasaki J, Aoyama Y, Hino M, et al. Wilms tumor 1 (WT1) mRNA expression level at diagnosis is a significant prognostic marker in elderly patients with myelodysplastic syndrome. Acta Haematol. 2017;137(1):32-9.
9. Santaliestra M, Garrido A, Carricondo M, et al. Bone marrow WT1 levels in patients with myeloid neoplasms treated with 5‐azacytidine: Identification of responding patients. Eur J Haematol. 2019;103(3):208-14.
10. Nomdedéu JF, Esquirol A, Carricondo M, et al. Bone marrow WT1 levels in allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplasia: clinically relevant time points and 100 copies threshold value. Biol Blood Marrow Transplant. 2018;24(1):55-63.
11. Casalegno‐Garduño R, Schmitt A, Spitschak A, et al. Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation. Int J Cancer. 2016;138(7):1792-801.
12. Ino K, Fuji S, Tajima K, et al. Clinical utility of Wilms' tumor 1 monitoring in patients with myeloid malignancy and prior allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23(10):1780-7.
13. Bahmani F, Shayanmanesh M, Safari M, et al. Bone marrow microenvironment in myelodysplastic neoplasms: insights into pathogenesis, biomarkers, and therapeutic targets. Cancer Cell Int. 2025;25(1):175.
14. Cilloni D, Gottardi E, Messa F, et al. Significant correlation between the degree of WT1 expression and the International Prognostic Scoring System Score in patients with myelodysplastic syndromes. J Clin Oncol. 2003;21(10):1988-95.
15. Tamura H, Dan K, Yokose N, et al. Prognostic significance of WT1 mRNA and anti-WT1 antibody levels in peripheral blood in patients with myelodysplastic syndromes. Leuk Res. 2010;34(8):986-90.
16. Ueda Y, Mizutani C, Nannya Y, et al. Clinical evaluation of WT1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes. Leuk Lymphoma. 2013;54(7):1450-8.
17. DeZern AE, Greenberg PL. The trajectory of prognostication and risk stratification for patients with myelodysplastic syndromes. Blood. 2023;142(26):2258-67.
18. Garcia‐Manero G. Myelodysplastic syndromes: 2023 update on diagnosis, risk‐stratification, and management. Am J Hematol. 2023;98(8):1307-25.
19. Mehralizadeh H, Aliparasti MR, Talebi M, et al. WT-1, BAALC, and ERG expressions in Iranian patients with acute myeloid leukemia pre-and post-chemotherapy. Adv Pharm Bull. 2021;11(1):197-203.
20. Gallo D, Nicoli P, Calabrese C, et al. The Wilms’ tumor (WT 1) gene expression correlates with the International Prognostic Scoring System (IPSS) score in patients with myelofibrosis and it is a marker of response to therapy. Cancer Med. 2016;5(7):1650-3.
21. Israyelyan A, Goldstein L, Tsai W, et al. Real-time assessment of relapse risk based on the WT1 marker in acute leukemia and myelodysplastic syndrome patients after hematopoietic cell transplantation. Bone Marrow Transplant. 2015;50(1):26-33.
22. Rautenberg C, Lauseker M, Kaivers J, et al. Prognostic impact of pretransplant measurable residual disease assessed by peripheral blood WT1‐mRNA expression in patients with AML and MDS. Eur J Haematol. 2021;107(2):283-92.
23. Giudice V, Gorrese M, Vitolo R, et al. WT1 expression levels combined with flow cytometry blast counts for risk stratification of acute myeloid leukemia and myelodysplastic syndromes. Biomedicines. 2021;9(4):387.
24. Huang QS, Wang JZ, Qin YZ, et al. Overexpression of WT1 and PRAME predicts poor outcomes of patients with myelodysplastic syndromes with thrombocytopenia. Blood Adv. 2019;3(21):3406-18.
25. Yang L, Han Y, Saurez Saiz F, et al. A tumor suppressor and oncogene: the WT1 story. Leukemia. 2007;21(5):868-76.
26. Svensson E, Vidovic K, Lassen C, et al. Deregulation of the Wilms' tumour gene 1 protein (WT1) by BCR/ABL1 mediates resistance to imatinib in human leukaemia cells. Leukemia. 2007;21(12):2485-94.
27. Zhou B, Jin X, Jin W, et al. WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target. J Transl Med. 2020;18(1):254.
28. Rostami S, Kazemi A, Chahardouli B, et al. The Prognostic Impact of WT1 Expression Levels, Mutations, and SNP rs16754 in AML Patients: A Retrospective Cohort Study. J Adv Med Biomed Res. 2021;29(133):109-17.
29. Lyu Y, Lou J, Yang Y, et al. Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and-independent pathways. Leukemia. 2017;31(12):2543-51.
30. Sugiyama H. Wilms Tumor Gene WT1 as a: Tumor Marker for Leukemic Blast Cells and Its Role in Leukemogenesis. Methods Mol Med. 2002:68:223-37.
31. Potluri S, Assi SA, Chin PS, et al. Isoform-specific and signaling-dependent propagation of acute myeloid leukemia by Wilms tumor 1. Cell Rep. 2021;35(3):109010.
32. Kobayashi S, Ueda Y, Kurokawa M, et al. WT-1 Expression Level In BM Is The Great Prognostic Marker In Three Of Classification IPSS, WPSS, and Latest Revised IPSS (IPSS-R). Blood. 2013;122(21):2795.
33. Heuser M, Thol F, Ganser A. Clonal Hematopoiesis of Indeterminate Potential. Dtsch Arztebl Int. 2016;113(18):317-22.
34. Parmentier S, Schetelig J, Lorenz K, et al. Assessment of dysplastic hematopoiesis: lessons from healthy bone marrow donors. Haematologica. 2012;97(5):723-730..
35. Senent L, Arenillas L, Luño E, et al. Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes. Haematologica. 2013;98(4):568-575.
36. Valent P, Orazi A, Steensma DP, et al. Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions. Oncotarget. 2017;8(43):73483-73500.
37. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9-16.
38. Ariste O, de la Grange P, Veitia RA. Recurrent missense variants in clonal hematopoiesis‐related genes present in the general population. Clin Genet. 2023;103(2):247-51.
39. Pritzl SL, Badar T, Ferrer A, et al. U2AF1 Mutant Clonal Hematopoiesis Is Infrequent, Context Dependent, and Commonly Co-Occurs with BCOR Mutations. Blood. 2022;140(Supplement 1):11408-9.
2. Oji Y, Nakamori S, Fujikawa M, et al. Overexpression of the Wilms' tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci. 2004;95(7):583-7.
3. Rampal R, Figueroa ME. Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia. Haematologica. 2016;101(6):672-9.
4. Rautenberg C, Germing U, Pechtel S, et al. Prognostic impact of peripheral blood WT1-mRNA expression in patients with MDS. Blood Cancer J. 2019;9(11):86.
5. Cilloni D, Renneville A, Hermitte F, et al. 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. 2009;27(31):5195-201.
6. Bergmann L, Miething C, Maurer U, et al. High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood. 1997;90(3):1217-25.
7. Hou HA, Huang TC, Lin LI, et al. 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. 2010;115(25):5222-31.
8. Nagasaki J, Aoyama Y, Hino M, et al. Wilms tumor 1 (WT1) mRNA expression level at diagnosis is a significant prognostic marker in elderly patients with myelodysplastic syndrome. Acta Haematol. 2017;137(1):32-9.
9. Santaliestra M, Garrido A, Carricondo M, et al. Bone marrow WT1 levels in patients with myeloid neoplasms treated with 5‐azacytidine: Identification of responding patients. Eur J Haematol. 2019;103(3):208-14.
10. Nomdedéu JF, Esquirol A, Carricondo M, et al. Bone marrow WT1 levels in allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplasia: clinically relevant time points and 100 copies threshold value. Biol Blood Marrow Transplant. 2018;24(1):55-63.
11. Casalegno‐Garduño R, Schmitt A, Spitschak A, et al. Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation. Int J Cancer. 2016;138(7):1792-801.
12. Ino K, Fuji S, Tajima K, et al. Clinical utility of Wilms' tumor 1 monitoring in patients with myeloid malignancy and prior allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23(10):1780-7.
13. Bahmani F, Shayanmanesh M, Safari M, et al. Bone marrow microenvironment in myelodysplastic neoplasms: insights into pathogenesis, biomarkers, and therapeutic targets. Cancer Cell Int. 2025;25(1):175.
14. Cilloni D, Gottardi E, Messa F, et al. Significant correlation between the degree of WT1 expression and the International Prognostic Scoring System Score in patients with myelodysplastic syndromes. J Clin Oncol. 2003;21(10):1988-95.
15. Tamura H, Dan K, Yokose N, et al. Prognostic significance of WT1 mRNA and anti-WT1 antibody levels in peripheral blood in patients with myelodysplastic syndromes. Leuk Res. 2010;34(8):986-90.
16. Ueda Y, Mizutani C, Nannya Y, et al. Clinical evaluation of WT1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes. Leuk Lymphoma. 2013;54(7):1450-8.
17. DeZern AE, Greenberg PL. The trajectory of prognostication and risk stratification for patients with myelodysplastic syndromes. Blood. 2023;142(26):2258-67.
18. Garcia‐Manero G. Myelodysplastic syndromes: 2023 update on diagnosis, risk‐stratification, and management. Am J Hematol. 2023;98(8):1307-25.
19. Mehralizadeh H, Aliparasti MR, Talebi M, et al. WT-1, BAALC, and ERG expressions in Iranian patients with acute myeloid leukemia pre-and post-chemotherapy. Adv Pharm Bull. 2021;11(1):197-203.
20. Gallo D, Nicoli P, Calabrese C, et al. The Wilms’ tumor (WT 1) gene expression correlates with the International Prognostic Scoring System (IPSS) score in patients with myelofibrosis and it is a marker of response to therapy. Cancer Med. 2016;5(7):1650-3.
21. Israyelyan A, Goldstein L, Tsai W, et al. Real-time assessment of relapse risk based on the WT1 marker in acute leukemia and myelodysplastic syndrome patients after hematopoietic cell transplantation. Bone Marrow Transplant. 2015;50(1):26-33.
22. Rautenberg C, Lauseker M, Kaivers J, et al. Prognostic impact of pretransplant measurable residual disease assessed by peripheral blood WT1‐mRNA expression in patients with AML and MDS. Eur J Haematol. 2021;107(2):283-92.
23. Giudice V, Gorrese M, Vitolo R, et al. WT1 expression levels combined with flow cytometry blast counts for risk stratification of acute myeloid leukemia and myelodysplastic syndromes. Biomedicines. 2021;9(4):387.
24. Huang QS, Wang JZ, Qin YZ, et al. Overexpression of WT1 and PRAME predicts poor outcomes of patients with myelodysplastic syndromes with thrombocytopenia. Blood Adv. 2019;3(21):3406-18.
25. Yang L, Han Y, Saurez Saiz F, et al. A tumor suppressor and oncogene: the WT1 story. Leukemia. 2007;21(5):868-76.
26. Svensson E, Vidovic K, Lassen C, et al. Deregulation of the Wilms' tumour gene 1 protein (WT1) by BCR/ABL1 mediates resistance to imatinib in human leukaemia cells. Leukemia. 2007;21(12):2485-94.
27. Zhou B, Jin X, Jin W, et al. WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target. J Transl Med. 2020;18(1):254.
28. Rostami S, Kazemi A, Chahardouli B, et al. The Prognostic Impact of WT1 Expression Levels, Mutations, and SNP rs16754 in AML Patients: A Retrospective Cohort Study. J Adv Med Biomed Res. 2021;29(133):109-17.
29. Lyu Y, Lou J, Yang Y, et al. Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and-independent pathways. Leukemia. 2017;31(12):2543-51.
30. Sugiyama H. Wilms Tumor Gene WT1 as a: Tumor Marker for Leukemic Blast Cells and Its Role in Leukemogenesis. Methods Mol Med. 2002:68:223-37.
31. Potluri S, Assi SA, Chin PS, et al. Isoform-specific and signaling-dependent propagation of acute myeloid leukemia by Wilms tumor 1. Cell Rep. 2021;35(3):109010.
32. Kobayashi S, Ueda Y, Kurokawa M, et al. WT-1 Expression Level In BM Is The Great Prognostic Marker In Three Of Classification IPSS, WPSS, and Latest Revised IPSS (IPSS-R). Blood. 2013;122(21):2795.
33. Heuser M, Thol F, Ganser A. Clonal Hematopoiesis of Indeterminate Potential. Dtsch Arztebl Int. 2016;113(18):317-22.
34. Parmentier S, Schetelig J, Lorenz K, et al. Assessment of dysplastic hematopoiesis: lessons from healthy bone marrow donors. Haematologica. 2012;97(5):723-730..
35. Senent L, Arenillas L, Luño E, et al. Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes. Haematologica. 2013;98(4):568-575.
36. Valent P, Orazi A, Steensma DP, et al. Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions. Oncotarget. 2017;8(43):73483-73500.
37. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9-16.
38. Ariste O, de la Grange P, Veitia RA. Recurrent missense variants in clonal hematopoiesis‐related genes present in the general population. Clin Genet. 2023;103(2):247-51.
39. Pritzl SL, Badar T, Ferrer A, et al. U2AF1 Mutant Clonal Hematopoiesis Is Infrequent, Context Dependent, and Commonly Co-Occurs with BCOR Mutations. Blood. 2022;140(Supplement 1):11408-9.
| Files | ||
| Issue | Vol 20 No 1 (2026): Articles In Press | |
| Section | Original Article(s) | |
| Keywords | ||
| Myelodysplastic; Wilms’ tumor 1 (WT1) proteins; Prognosis; Survival analysis | ||
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How to Cite
1.
Bahmani F, Zaker F, Chahardouli B, Safa M, Alizadghandforoush N, Mohammadi S, Nikbakht M, Rostami S, Janbabaei G. WT1 as a Biomarker in Myelodysplastic Neoplasms: Clinical Correlations and Preliminary Data from an Iranian Cohort. Int J Hematol Oncol Stem Cell Res. 2026;20(1).
