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Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer representing 23% of pediatric cancers. Wilms' tumor -1 gene has is a novel prognostic factor, minimal residual disease marker and therapeutic target in acute leukemia. Aim of the work: The aim of this work was to study the impact of WT-1 gene expression in prognosis of Egyptian children with ALL. Patients and methods: This study was conducted on 40 children with newly diagnosed ALL who were subjected to full history taking, thorough clinical examination and laboratory investigations including; complete blood count, LDH, BM aspiration, cytochemistry, immunophenotyping, assessment of WT-1 Gene by real time PCR in BM samples at time of diagnosis. Results: Positive WT-1 gene expression was found in 22 cases (55%) and negative expression in 18 cases (45%). Positive WT-1 gene expression group (n=22) includes 14 males and 8 females with mean age at presentation of 5.261 ± 0.811 while negative WT-1 gene expression group (n=18) includes 12 males and 6 females with mean age at diagnosis of 9.669 ± 3.731 with significantly older age in negative WT-1 gene expression group but no significant differences between positive and negative WT-1 gene expression groups regarding sex and clinical presentations. There were no significant differences in platelets and WBCs counts, hemoglobin and LDH levels and number of peripheral blood and BM blast cells at diagnosis between positive and negative WT-1 gene expression groups but after induction therapy there were significantly lower BM blast cells in positive WT-1 gene expression group. There were no statistically significant differences between positive and negative WT-1 gene expression groups regarding immunophenotyping. There were significantly higher relapse and death rates and lower rates of CR, DFS and OAS in negativeWT-1 gene expression group.MRD at end of induction therapy was found in 14 cases out of 40 patients. There was significantly higher number of cases with MRD in negative WT-1 gene expression group (In 26 cases with negative MRD; 20 have positive WT-1 gene expression and 6 have negative WT-1gene expression while in 14 cases with positive MRD ; 12 cases showed negative WT-1 gene expression and 2 cases showed positive WT-1 gene expression) (p value = 0.006). Conclusions and Recommendation: WT-1 gene expression is important prognostic factor in patients with ALL and therefore we recommend its incorporation into novel risk-adapted therapeutic strategies in patients with ALL.
1. Shah A and Coleman MP. Increasing incidence of childhood leukemia: A controversy re-examined. Br J Cancer 2007; 97(7): 1009-1012.
2. Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, Reaman GH, Carroll WL. Improved Survival for Children and Adolescents with Acute Lymphoblastic Leukemia Between 1990 and 2005: A Report from the Children's Oncology Group. J Clin Oncol 2012 May 10; 30(14):1663-9. doi: 10.1200/JCO.2011.37.8018. Epub 2012 Mar 12.
3. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; Jun 25; 360(26):2730-41. doi: 10.1056/NEJMoa0900386.
4. Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, Ludwig WD, Ritter J, Harbott J, Mann G, Klingebiel T, Zintl F, Niemeyer C, Kremens B, Niggli F, Niethammer D, Welte K, Stanulla M, Odenwald E, Riehm H, Schrappe M. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010 Feb; 24(2):265-84. doi: 10.1038/leu.2009.257. Epub 2009 Dec 10
5. Campana D: Role of minimal residual disease monitoring in adult and pediatric acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2009; 23:1083–1098.
6. Stow P, Key L, Chen X, Pan Q, Neale GA, Coustan-Smith E, Mullighan CG, Zhou Y, Pui CH, Campana D. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood 2010 Jun 10; 115(23):4657-63. doi: 10.1182/blood-2009-11-253435. Epub 2010 Mar 19.
7. Cilloni D, Gottardi E, Fava M, Messa F, Carturan S, Busca A, Guerrasio A, Saglio G. Usefulness of quantitative assessment of the WT1 gene transcript as a marker for minimal residual disease detection. Blood 2003 Jul 15; 102(2):773–774.
8. Oji Y, Miyoshi S, Maeda H, Hayashi S, Tamaki H, Nakatsuka S, Yao M, Takahashi E, Nakano Y, Hirabayashi H, Shintani Y, Oka Y, Tsuboi A, Hosen N, Asada M, Fujioka T, Murakami M, Kanato K, Motomura M, Kim EH, Kawakami M, Ikegame K, Ogawa H, Aozasa K, Kawase I, Sugiyama H. Overexpression of Wilms’ tumor gene in de novo lung cancers. Int J Cancer. 2002 Jul 20; 100(3):297-303.
9. Ostergaard M, Olesen LH, Hasle H, Kjeldsen E, Hokland P.. WT1 gene expression: An excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukemia patients. Results from a single –centre study. Br J Haematol 2004 Jun; 125(5):590–600.
10. Ching-Hon Pui. Acute lymphoplastic leukemia: Overview. In: Lichtman MA, Beulter E, Seligsonn U, Kipps TO, Kaushansky K, Prchal J (editors). William Textbook of Hematology. 17th edition, Chapter 91. New York: McGraw-Hill Companies, Inc.; Part XI: Neoplastic Lymphoid Diseases, 2007; 91: 1141-53.
11. Chauvenet AR, Martin PL, Devidas M, Linda SB, Bell BA, Kurtzberg J, Pullen J, Pettenati MJ, Carroll AJ, Shuster JJ, Camitta B. Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from the Children’s Oncology Group Study P9201. Blood 2007 Aug 15; 110(4):1105-11. Epub 2007 Apr 18 .
12. Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, Freyer DR, Mattano LA Jr, Hastings CA, Rubin CM, Bertolone K, Franklin JL, Heerema NA, Mitchell TL, Pyesmany AF, La MK, Edens C, Gaynon PS. Early post induction intensification therapy improves survival for children and adolescents with high risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood 2008 Mar 1; 111(5):2548-55. Epub 2007 Nov 26.
13. Lanzkowsky PH. Leukemias. In: Lanzkowsky Philip (editor), Manual of Pediatric Hematology and Oncology. 5th ed. Churchill livingstane. Nek, London, Madrid, 2011; 17: 518- 566.
14. Goldberg JM, Silverman LB, Levy DE, Dalton VK, Gelber RD, Lehmann L, Cohen HJ, Sallan SE, Asselin BL. Childhood T cell acute lymphoblastic leukemia. The Dana-Farber Cancer Institute. Acute Lymphoblastic Leukemia Consortium experience. J Clin Oncol 2003 Oct 1; 21(19):3616-22.
15. Catovsky D and Hoffbrand AV. Acute myeloid leukaemia. In: A.V. Hoffbrand and S.M. Lewis (eds) Postgraduate Haematology, 5th edition, Oxford, UK: Reed Educational and Professional Publishing Ltd. 2005; 509-524.
16. Boyam A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of mononuclear cells by one centrifugation and of granulocytes by combining centrifugation and sedimentation at 1g. Scand J Clin Lab Invest Suppl. 1968; 77:97-99.
17. Petrie A and Sabin C. Medical statistics at a glance. Blackwell Publishing, Oxford, 2nd edition, 2005; 978(1):4051-8051.
18. Ribera JM and Oriol A. Acute lymphoblastic leukemia in adolescents and young adults. Hematol Oncol Clin North Am: 2009; 23(5):1033-1042.
19. Brüggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M, Ottmann OG, Asnafi V, Baruchel A, Bassan R, Benoit Y, Biondi A, Cavé H, Dombret H, Fielding AK, Foà R, Gökbuget N, Goldstone AH, Goulden N, Henze G, Hoelzer D, Janka-Schaub GE, Macintyre EA, Pieters R, Rambaldi A, Ribera JM, Schmiegelow K, Spinelli O, Stary J, von Stackelberg A, Kneba M, Schrappe M, van Dongen JJ; European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL); International Berlin-Frankfurt-Münster Study Group (I-BFM-SG). Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany. Leukemia 2010 Mar; 24(3):521–535. doi: 10.1038/leu.2009.268. Epub 2009 Dec 24.
20. Barragán E, Cervera J, Bolufer P, Ballester S, Martín G, Fernández P, Collado R, Sayas MJ, Sanz MA. Prognostic implications of Wilms' tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica 2004 Aug; 89(8): 926–933.
21. Boublikova L, Kalinova M, Ryan J, Quinn F, O'Marcaigh A, Smith O, Browne P, Stary J, McCann SR, Trka J, Lawler M. Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: A wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring, Leukemia 2006 Feb; 20 (2):254–263.
22. Kerst G, Kreyenberg H, Roth C, Well C, Dietz K, Coustan-Smith E, Campana D, Koscielniak E, Niemeyer C, Schlegel PG, Müller I, Niethammer D, Bader P. Concurrent detection of minimal residual disease in childhood ALL by flow cytometry and real-time PCR. Br J Haematol 2005 Mar; 128 (6): 774–782.
23. Sadek HA, El-Metnawey WH, Shaheen IA, Korshied MM, Mohamed AS. Quantitative assessment of WT1 Gene transcripts in Egyptian acute lymphoblastic leukemia Patients: Journal of Investigative Medicine 2011 Dec; 59(8): 1258-1262. doi: 10.231/JIM.0b013e31822a24f7.
24.Liu HS, Zhu MS, Zhang HL, Wei SY, Wang XN, Xi XP, Yu FF, Xi JY, Wang MC, Zhang M. WT1 gene expression difference in leukemia and non- leukemia and its clinical significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2014 Oct; 22(5):1217-21. doi: 10.7534/j.issn. 1009-2137.2014.05.005.
25. Zhang R, Yang JY, Sun HQ, Jia H, Liao J, Shi YJ, Li G. Comparison of minimal residual disease (MRD) monitoring by WT1 quantification between childhood acute myeloid leukemia and acute lymphoblastic leukemia. Eur Rev Med Pharmacol Sci. 2015 Jul; 19(14):2679-88
26. Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM; Children's Oncology Group. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: A Children's Oncology Group study. Blood 2008 Jun 15; 111 (12): 5477-5485. doi: 10.1182/blood-2008-01-132837. Epub 2008 Apr 3.