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Is Wilms’ tumor gene 1 a useful biomarker for detecting minimal residual disease in chronic myeloid leukemia (BCR-ABL1-p210-positive) patients?

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Abstract

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the presence of Philadelphia (Ph) chromosome. Wilms’ tumor gene 1 (WT1) plays an important role in leukemogenesis and can be useful as a molecular marker to detect minimal residual disease (MRD). The goal of this study was to evaluate WT1 expression and compare it with BCR-ABL1 expression in peripheral blood (PB) of CML patients, in order to explore the utility of WT1 as an alternative marker for MRD detection. Eighteen newly diagnosed CML patients (BCR-ABL1-p210-positive), 16 chronic CML patients with a history of imatinib therapy, and 18 normal individuals (BCR-ABL1-p210-negative) as controls were enrolled in this study. WT1 and BCR-ABL1 expression was evaluated by quantitative real-time polymerase chain reaction (Q-RT-PCR). Analysis of RT-PCR data was performed using REST Software (2009, QIAGEN, Valencia, USA). Data were analyzed by SPSS software (v.16.0) using Spearman’s rho and Kruskal-Wallis methods. WT1 expression in all PB samples of newly diagnosed CML patients was significantly higher than that of the normal individuals (P = 0.003). WT1 expression was not different in patients on imatinib therapy compared to normal individuals (P = 0.6), but it was significantly lower than that of the newly diagnosed CML patients (P = 0.001). There was no significant correlation between expression of WT1 and BCR-ABL1 and hematological findings in newly diagnosed CML patients. We confirm the oncogenic role of WT1 by WT1 upregulation in CML. Due to lack of significant correlation between BCR-ABL1 and WT1 expression, using WT1 as an additional marker for CML monitoring could not be applicable.

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References

  • Asgarian Omran H, Shabani M, Vossough P, Sharifian R, Tabrizi M, Khoshnoodi J et al (2008) Cross-sectional monitoring of Wilms’ tumor gene 1 (WT1) expression in Iranian patients with acute lymphoblastic leukemia at diagnosis, relapse and remission. Leuk Lymphoma 49(2):281–290

    Article  PubMed  Google Scholar 

  • Asgarian H, Shabani M, Vosoogh P, Ali R, Sharifian SG, Khoshnoodi J et al (2005) Over-expression of Wilm’s Tumor Gene 1 (WT1) in Iranian patients with acute myeloblastic leukemia. Iran J Immunol 2(4):182

    Google Scholar 

  • Babashah S, Rezaei-Tavirani M, Zamanian-Azodi M, Saki N (2012) Chronic myeloid leukemia as a stem cell-derived malignancy. J Paramedical Sci. 3(2)

  • Burchert A, Cai D, Hofbauer LC, Samuelsson MK, Slater EP, Duyster J et al (2004) Interferon consensus sequence binding protein (ICSBP; IRF-8) antagonizes BCR/ABL and down-regulates bcl-2. Blood 103(9):3480–3489

    Article  CAS  PubMed  Google Scholar 

  • Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M et al (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55(4):611–622

    Article  CAS  PubMed  Google Scholar 

  • Calabretta B, Perrotti D (2004) The biology of CML blast crisis. Blood 103(11):4010–4022

    Article  CAS  PubMed  Google Scholar 

  • Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA et al (1990) Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 60(3):509–520

    Article  CAS  PubMed  Google Scholar 

  • Cao XS, Gu WY, Chen ZX, Hu SY, He J, Cen JN (2007) Bone marrow WT1 gene expression and clinical significance in chronic myelogenous leukemia. Zhonghua Nei Ke Za Zhi 46(4):277–279

    CAS  PubMed  Google Scholar 

  • Cilloni D, Saglio G, editors (2003) Usefulness of quantitative assessment of Wilms tumor suppressor gene expression in chronic myeloid leukemia patients undergoing imatinib therapy. Seminars in Hematology: Elsevier

  • Cilloni D, Messa F, Gottardi E, Fava M, Arruga F, Defilippi I et al (2004) Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation. Cancer 101(5):979–988

    Article  CAS  PubMed  Google Scholar 

  • Cilloni D, Renneville A, Hermitte F, Hills RK, Daly S, Jovanovic JV et al (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(31):5195–5201

    Article  CAS  PubMed  Google Scholar 

  • Corrêa S, Binato R, Du Rocher B, Castelo-Branco MT, Pizzatti L, Abdelhay E (2012) Wnt/β-catenin pathway regulates ABCB1 transcription in chronic myeloid leukemia. BMC Cancer 12(1):303

    Article  PubMed  PubMed Central  Google Scholar 

  • Dong W, Zhang J, Shao N, Tian T, Li L, Jian J et al (2014) Development and immunological evaluation of HLA-specific chronic myeloid leukemia polyepitope vaccine in Chinese population. Vaccine 32(28):3501–3508

    Article  CAS  PubMed  Google Scholar 

  • Glienke W, Maute L, Koehl U, Esser R, Milz E, Bergmann L (2007) Effective treatment of leukemic cell lines with wt1 siRNA. Leukemia 21(10):2164–2170

    Article  CAS  PubMed  Google Scholar 

  • Hatta Y, Takeuchi J, Saitoh T, Itoh T, Ishizuka H, Iriyama N et al (2005) WT1 expression level and clinical factors in multiple myeloma. J Exp Clin Cancer Res 24(4):595

    CAS  PubMed  Google Scholar 

  • Heesch S, Goekbuget N, Stroux A, Tanchez JO, Schlee C, Burmeister T et al (2010) Prognostic implications of mutations and expression of the Wilms tumor 1 (WT1) gene in adult acute T-lymphoblastic leukemia. Haematologica 95(6):942–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H et al (1994) WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 84(9):3071–3079

    CAS  PubMed  Google Scholar 

  • Inoue K, Tamaki H, Ogawa H, Oka Y, Soma T, Tatekawa T et al (1998) Wilms’ tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells. Blood 91(8):2969–2976

    CAS  PubMed  Google Scholar 

  • Jabbour E, Kantarjian H (2014) Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am J Hematol 89(5):547–556

    Article  CAS  PubMed  Google Scholar 

  • Li X, Li Y, Yuan T, Zhang Q, Jia Y, Li Q, et al. (2014) Exogenous expression of WT1 gene influences U937 cell biological behaviors and activates MAPK and JAK-STAT signaling pathways. Leuk Res

  • Li Y, Wang J, Li X, Jia Y, Huai L, He K et al (2014b) Role of the Wilms’ tumor 1 gene in the aberrant biological behavior of leukemic cells and the related mechanisms. Oncol Rep 32(6):2680–2686

    CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  • Mao X, Zhang B, Liu L-L, Bai X-L, Zhang D-H (2013) Interaction of human genes WT1 and CML28 in leukemic cells. J Huazhong Univ Sci Technol Med Sci 33:37–42

    Article  CAS  PubMed  Google Scholar 

  • Maurer U, Brieger J, Weidmann E, Mitrou P, Hoelzer D, Bergmann L (1997) The Wilms’ tumor gene is expressed in a subset of CD34+ progenitors and downregulated early in the course of differentiation in vitro. Exp Hematol 25(9):945–950

    CAS  PubMed  Google Scholar 

  • Menssen HD, Renkl H-J, Entezami M, Thiel E (1997) Wilms’ tumor gene expression in human CD34+ hematopoietic progenitors during fetal development and early clonogenic growth. Blood 89(9):3486

    CAS  PubMed  Google Scholar 

  • Nishida S, Hosen N, Shirakata T, Kanato K, Yanagihara M, Nakatsuka S-i et al (2006) AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. Blood 107(8):3303–3312

    Article  CAS  PubMed  Google Scholar 

  • Nomdedéu J, Hoyos M, Carricondo M, Bussaglia E, Estivill C, Esteve J, et al. (2013) Bone marrow WT1 levels at diagnosis, post-induction and post-intensification in adult de novo AML. Leukemia

  • Otahalova E, Ullmannova-Benson V, Klamova H, Haskovec C (2008) WT1 expression in peripheral leukocytes of patients with chronic myeloid leukemia serves for the prediction of Imatinib resistance. Neoplasma 56(5):393–397

    Article  Google Scholar 

  • Sakamoto Y, Mariya Y, Sasaki S, Teshiromori R, Oshikiri T, Segawa M et al (2009) WT1 mRNA level in peripheral blood is a sensitive biomarker for monitoring minimal residual disease in acute myeloid leukemia. Tohoku J Exp Med 219(2):169–176

    Article  CAS  PubMed  Google Scholar 

  • Schmidt M, Bies J, Tamura T, Ozato K, Wolff L (2004) The interferon regulatory factor ICSBP/IRF-8 in combination with PU. 1 up-regulates expression of tumor suppressor p15Ink4b in murine myeloid cells. Blood 103(11):4142–4149

    Article  CAS  PubMed  Google Scholar 

  • Siehl JM, Reinwald M, Heufelder K, Menssen HD, Keilholz U, Thiel E (2004) Expression of Wilms’ tumor gene 1 at different stages of acute myeloid leukemia and analysis of its major splice variants. Ann Hematol 83(12):745–750

    Article  PubMed  Google Scholar 

  • Smith DL, Burthem J, Whetton AD (2003) Molecular pathogenesis of chronic myeloid leukaemia. Expert Rev Mol Med 5(27):1–27

    Article  CAS  PubMed  Google Scholar 

  • Sugiyama H (2010) WT1 (Wilms’ tumor gene 1): biology and cancer immunotherapy. Jpn J Clin Oncol 40(5):377–387

    Article  PubMed  Google Scholar 

  • Svensson E, Vidovic K, Lassen C, Richter J, Olofsson T, Fioretos T et al (2007a) Deregulation of the Wilms’ tumour gene 1 protein (WT1) by BCR/ABL1 mediates resistance to imatinib in human leukaemia cells. Leukemia 21(12):2485–2494

    Article  CAS  PubMed  Google Scholar 

  • Svensson E, Vidovic K, Olofsson T, Vallon-Christersson J, Borg Å, Gullberg U (2007b) The Wilms’ tumor gene 1 (WT1) induces expression of the N-myc downstream regulated gene 2 (NDRG2). DNA Cell Biol 26(8):589–597

    Article  CAS  PubMed  Google Scholar 

  • Swerdllow S, Campo E, Harris NL (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC Press, France

    Google Scholar 

  • Tamaki H, Ogawa H, Ohyashiki K, Ohyashiki J, Iwama H, Inoue K et al (1999) The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia 13(3):393–399

    Article  CAS  PubMed  Google Scholar 

  • Varma N, Anand MS, Varma S, Juneja SS (2011) Role of hTERT and WT1 gene expression in disease progression and imatinib responsiveness of patients with BCR-ABL positive chronic myeloid leukemia. Leuk Lymphoma 52(4):687–693

    Article  CAS  PubMed  Google Scholar 

  • Vidovic K, Svensson E, Nilsson B, Thuresson B, Olofsson T, Lennartsson A et al (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(5):992–1000

    Article  CAS  PubMed  Google Scholar 

  • Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M et al (1996) Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. Blood 87(7):2878–2884

    CAS  PubMed  Google Scholar 

  • Yang L, Han Y, Saiz FS, Minden M (2007) A tumor suppressor and oncogene: the WT1 story. Leukemia 21(5):868–876

    CAS  PubMed  Google Scholar 

  • Zheng C, Li L, Haak M, Brors B, Frank O, Giehl M et al (2006) Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis. Leukemia 20(6):1028–1034

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was financially supported by grant TH92/13 from the Vice Chancellor for Research Affairs of the Ahvaz Jundishapur University of Medical Sciences. This paper is issued from the thesis of Saeideh Hajizamani.

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Authors and Affiliations

  1. Health Research Institute, Thalassemia and Hemoglobinopathy Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Saeideh Hajizamani, Amal Saki Malehi, Ahmad Ahmadzadeh, Tina Vosoughi, Mohammad Seghatoleslami & Najmaldin Saki

  2. Department of Medical Genetics, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Javad Mohammadi-asl

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  1. Saeideh Hajizamani
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  2. Javad Mohammadi-asl
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  3. Amal Saki Malehi
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  4. Ahmad Ahmadzadeh
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  5. Tina Vosoughi
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  6. Mohammad Seghatoleslami
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  7. Najmaldin Saki
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Correspondence to Najmaldin Saki.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the local ethics committee of the Ahvaz Jundishapur University of Medical Sciences (ajums.REC.1392, 341) and with the 1964 Helsinki declaration. Written informed consent was obtained from all patients and normal individuals.

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Hajizamani, S., Mohammadi-asl, J., Malehi, A.S. et al. Is Wilms’ tumor gene 1 a useful biomarker for detecting minimal residual disease in chronic myeloid leukemia (BCR-ABL1-p210-positive) patients?. Comp Clin Pathol 25, 713–720 (2016). https://doi.org/10.1007/s00580-016-2252-y

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  • DOI: https://doi.org/10.1007/s00580-016-2252-y

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