DOI QR코드

DOI QR Code

Clinical Impact of Overexpression of FOXP3 and WT1 on Disease Outcome in Egyptian Acute Myeloid Leukemia Patients

  • Assem, Magda M (Department of Clinical Pathology, National Cancer Institute (NCI), Cairo university) ;
  • Osman, Ahmed (Department of Biochemistry, Faculty of Science, Ain Shams University) ;
  • Kandeel, Eman Z (Department of Clinical Pathology, National Cancer Institute (NCI), Cairo university) ;
  • Elshimy, Reham AA (Department of Clinical Pathology, National Cancer Institute (NCI), Cairo university) ;
  • Nassar, Hanan R (Medical Oncology, National Cancer Institute (NCI), Cairo university) ;
  • Ali, Radwa E (Department of Biochemistry, Faculty of Science, Ain Shams University)
  • Published : 2016.10.01

Abstract

Background: In the last decade, it has become clear that change of gene expression may alter the hematopoietic cell quiescent state and consequently play a major role in leukemogenesis. WT1 is known to be a player in acute myeloid leukemia (AML) and FOXP3 has a crucial role in regulating the immune response. Objectives: To evaluate the impact of overexpression of WT1and FOXP3 genes on clinical course in adult and pediatric AML patients in Egypt. Patients and methods: Bone marrow and peripheral blood samples were obtained from 97 de novo non M3 AML patients (63 adult and 34 pediatric). Real-time quantitative PCR was used to detect overexpression WT1 and FOXP3 genes. Patient follow up ranged from 0.2 to 39.0 months with a median of 5 months. Results: In the pediatric group; WT1 was significantly expressed with a high total leukocyte count median 50X109/L (p=0.018). In the adult group, WT1 had an adverse impact on complete remission induction, disease-free survival and overall survival (p=0.02, p=0.035, p=0.019 respectively). FOXP3 overexpression was associated with FAB subtypes AML M0 +M1 vs. M2, M4+M5 (p =0.039) and the presence of hepatomegaly (p=0.005). Conclusions: WT1 and FOXP3 overexpression has an adverse impact on clinical presentation, treatment response and survival of pediatric and adult Egyptian AML patients.

Keywords

AML;WT1;FOXP3

References

  1. Ho PA, Alonzo TA, Gerbing RB, et al (2014). The prognostic effect of high diagnostic WT1 gene expression in pediatric AML depends on WT1 SNP rs16754 status: report from the children's oncology group. Pediatr Blood Cancer, 61, 81-8. https://doi.org/10.1002/pbc.24700
  2. Hamed N, El-Halawani N, Nafie D, Swelem R, Araby A (2015). Regulatory T Cells in egyptian acute myeloid leukemia patients. Acta Med Int, 2, 134-7. https://doi.org/10.5530/ami.2015.1.23
  3. Inoue K, Sugiyama H, Ogawa 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, 3071-9.
  4. Ibrahim A, Badrawy H, Sayed H(2015).Prognostic implications of expression of the wilms tumor 1 (WT1) gene in acute leukemia (experience from south egypt). Br J Med Med Res, 7, 61-71. https://doi.org/10.9734/BJMMR/2015/15834
  5. Karakas T, Miething C, Maurer U, et al (2002). The coexpression of the apoptosis-related genes BCL-2 and WT1 in predicting survival in adult acute myeloid leukemia. Leukemia, 16, 846-9. https://doi.org/10.1038/sj.leu.2402434
  6. Kantarjian H, O'Brien S, Cortes J, et al (2008). Therapeutic advances in leukemia and myelodysplastic syndrome over the past 40 years. Cancer, 113, 1933-52. https://doi.org/10.1002/cncr.23655
  7. Yang W, Xu Y (2013). Clinical significance of Treg cell frequency in acute myeloid leukemia. Int J hematol, 98, 558-62. https://doi.org/10.1007/s12185-013-1436-3
  8. Assem M, Raslan H, Salem S, et al (2013). Combined CD86 expression and increase in soluble vascular endothelial growth factor confers bad prognosis in adult acute myeloid leukemia. Life Sci J ,10, 1155-62.
  9. Bergmann L, Miething C, Maurer U, et al (1997). High levels of wilms' tumor gene (WT1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood, 90, 1217-25.
  10. Barragan E, Cervera J, Bolufer P, et al (2004). Prognostic implications of wilms' tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica, 89,926-33.
  11. Clavel J, Goubin A, Auclerc M-F, et al (2004). Incidence of childhood leukaemia and non-Hodgkin's lymphoma in france: national registry of childhood leukaemia and lymphoma, 1990-1999. Eur J Cancer Prev, 13, 97-103. https://doi.org/10.1097/00008469-200404000-00002
  12. Fontenot JD, Rudensky AY(2005). A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nature immunol, 6, 331-7. https://doi.org/10.1038/ni1179
  13. Gu W, Chen Z, Hu S, Shen H, Qiu G (2005). Cao X changes in expression of WT1 isoforms during induced differentiation of the NB4 cell line. Haematologica, 90, 403-5.
  14. Ustun C, Miller JS, Munn DH, Weisdorf DJ, Blazar BR (2011). Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?. Blood, 118, 5084-95. https://doi.org/10.1182/blood-2011-07-365817
  15. Woehlecke C, Wittig S, Arndt C, Gruhn B (2015). Prognostic impact of WT1 expression prior to hematopoietic stem cell transplantation in children with malignant hematological diseases. J Cancer Res Clin oncol, 141, 523-9. https://doi.org/10.1007/s00432-014-1832-y
  16. Mossallam GI, Abdel 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. https://doi.org/10.1179/1607845412Y.0000000048
  17. Ostergaard M, Olesen LH, Hasle H, Kjeldsen E, Hokland P (2004). WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients-results from a single-centre study. Br J haematol, 125, 590-600. https://doi.org/10.1111/j.1365-2141.2004.04952.x
  18. Patmasiriwat P, Fraizer G, Claxton D, Kantarjian H, Saunders G (1996). Expression pattern of WT1 and GATA-1 in AML with chromosome 16q22 abnormalities. Leukemia, 10, 1127-33.
  19. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ (2007). CD4+ CD25+ Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nature immunol, 8, 1353-62. https://doi.org/10.1038/ni1536
  20. Rooney CM (2014). Can Treg elimination enhance NK cell therapy for AML? Blood, 123, 3848-9. https://doi.org/10.1182/blood-2014-05-570291
  21. Schmid D, Heinze G, Linnerth B, et al (1997). Prognostic significance of WT1 gene expression at diagnosis in adult de novo acute myeloid leukemia. Leukemia, 11, 639-43. https://doi.org/10.1038/sj.leu.2400620
  22. Simpson LA, Burwell EA, Thompson KA, et al (2006). The antiapoptotic gene A1/BFL1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy. Blood, 107, 4695-702. https://doi.org/10.1182/blood-2005-10-4025
  23. Speletas M, Argentou N, Germanidis G, et al (2011). Foxp3 expression in liver correlates with the degree but not the cause of inflammation. Mediators Inflamm, 2011, 1-9.
  24. Szczepanski MJ, Szajnik M, Czystowska M, et al (2009). Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin Cancer Res, 15, 3325-32. https://doi.org/10.1158/1078-0432.CCR-08-3010
  25. Lapillonne H, Renneville A, Auvrignon A, et al (2006). High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol, 24, 1507-15. https://doi.org/10.1200/JCO.2005.03.5303
  26. Morrison AA, Viney RL, Ladomery MR (2008). The posttranscriptional roles of WT1, a multifunctional zinc-finger protein. Biochim Biophys Acta, 1785, 55-62.