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The Prognostic Relevance of BAALC and ERG Expression Levels in Cytogenetically Normal Pediatric Acute Myeloid Leukemia

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Abstract

Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). About 45 % of de novo adult AML and 20 % of pediatric AML lack cytogenetic abnormalities, so identification of predictive molecular markers might improve therapy. Mutation status of FLT3, NPM1 genes and gene expression levels of ERG, BAALC have been postulated as possible prognostic markers in pediatric AML with normal karyotype. Pretreatment blood samples from 47 cytogenetically normal AML patients were analysed for BAALC and ERG expression using real time RT-PCR. The patients were dichotomized at BAALC and ERG mean expression into low and high expression based on the median expression as cutoff. BAALC showed high expression in (24/47; 51.1 %) of patients and ERG high expression was detected in (22/47; 46.6 %). With follow-up for 1 year, patients with high BAALC and high ERG had inferior EFS (P = 0.001, P = 0.017 respectively), overall survival (P = 0.001, 0.08 respectively), and low rates of induction remission (P = 0.001, P = 0.0017 respectively) as compared to those with low expression. Also there was significant positive association between high expression of BAALC; ERG and FLT-ITD mutations (P = 0.016; P = 0.007 respectively). Multivariable analysis confirmed that high BAALC expression is an independent risk factor for EFS [HR for EFS 1.9(1.04–3.46) P = 0.037]; and OS [HR OS 1.55(1.7–3.36) P = 0.03]. In conclusion: Over expression of BAALC could predict adverse clinical outcome and may define important risk factor in cytogenetically normal pediatric AML.

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References

  1. Hermkens M, van den Heuvel-Eibrink M, Arentsen-Peters S, Baruchel A, Stary J, Reinhardt D (2013) The clinical relevance of BAALC and ERG expression levels in pediatric AML. Leukemia 27(3):735–737

    Article  CAS  PubMed  Google Scholar 

  2. Farag SS, Archer KJ, Mrózek K, Ruppert AS, Carroll AJ, Vardiman JW, Pettenati MJ, Baer MR, Qumsiyeh MB, Koduru PR, Ning Y, Mayer RJ, Stone RM, Larson RA, Bloomfield CD (2006) Pretreatment cytogenetics adds to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood 108(1):63–73

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Estey E (2007) Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol 25(14):1908–1915

    Article  PubMed  Google Scholar 

  4. Mrózek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD (2007) Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 109(2):431–448

    Article  PubMed Central  PubMed  Google Scholar 

  5. Döhner K, Schlenk RF, Habdank M, Scholl C, Rücker FG, Corbacioglu A, Bullinger L, Fröhling S, Döhner H (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106(12):3740–3746

    Article  PubMed  Google Scholar 

  6. Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C, Mrózek K, Baldus CD, Carroll AJ, Powell BL, Kolitz JE, Larson RA, Bloomfield CD, Cancer and Leukemia Group B Study (2007) High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 25(22):3337–3343

    Article  CAS  PubMed  Google Scholar 

  7. Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, Wermke M, Bornhäuser M, Ritter M, Neubauer A, Ehninger G, Illmer T (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99(12):4326–4335

    Article  CAS  PubMed  Google Scholar 

  8. Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, Wermke M, Bornhäuser M, Ritter M, Neubauer A, Ehninger G, Illmer T (2010) Mutations of the Wilms tumor 1 gene (WT1) in older patients with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood 116(5):788–792

    Article  Google Scholar 

  9. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD, European LeukemiaNet (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European Leukemia Net. Blood 115(3):453–474

    Article  PubMed  Google Scholar 

  10. Becker H, Marcucci G, Maharry K, Radmacher MD, Mrózek K, Margeson D, Whitman SP, Wu YZ, Schwind S, Paschka P, Powell BL, Carter TH, Kolitz JE, Wetzler M, Carroll AJ, Baer MR, Caligiuri MA, Larson RA, Bloomfield CD (2010) Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol 28(4):596–604

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Tanner SM, Austin JL, Leone G, Rush LJ, Plass C, Heinonen K, Mrózek K, Sill H, Knuutila S, Kolitz JE, Archer KJ, Caligiuri MA, Bloomfield CD, de La Chapelle A (2001) BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc Natl Acad Sci USA 98(24):13901–13906

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Ichikawa H, Shimizu K, Hayashi Y, Ohki M (1994) An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16, 21) chromosomal translocation. Cancer Res 54(11):2865–2868

    CAS  PubMed  Google Scholar 

  13. Baldus CD, Liyanarachchi S, Mrózek K, Auer H, Tanner SM, Guimond M, Ruppert AS, Mohamed N, Davuluri RV, Caligiuri MA, Bloomfield CD, de la Chapelle A (2004) Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA 101(11):3915–3920

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Mrózek K, Heinonen K, Theil KS, Bloomfield CD (2002) Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q. Genes Chromosom Cancer 34(2):137–153

    Article  PubMed  Google Scholar 

  15. Metzeler KH, Dufour A, Benthaus T, Hummel M, Sauerland MC, Heinecke A, Berdel WE, Büchner T, Wörmann B, Mansmann U, Braess J, Spiekermann K, Hiddemann W, Buske C, Bohlander SK (2009) ERG expression is an independent prognostic factor and allows refined risk stratification in cytogenetically normal acute myeloid leukemia: a comprehensive analysis of ERG, MN1, and BAALC transcript levels using oligonucleotide microarrays. J Clin Oncol 27(30):5031–5038

    Article  CAS  PubMed  Google Scholar 

  16. Marcucci G, Radmacher MD, Maharry K, Mrózek K, Ruppert AS, Paschka P, Vukosavljevic T, Whitman SP, Baldus CD, Langer C, Liu CG, Carroll AJ, Powell BL, Garzon R, Croce CM, Kolitz JE, Caligiuri MA, Larson RA, Bloomfield CD (2008) MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med 358(18):1919–1928

    Article  CAS  PubMed  Google Scholar 

  17. Klein JP, Moeschberger ML (1997) Survival analysis: techniques for censored and truncated. Springer, New York

    Book  Google Scholar 

  18. Langer C, Marcucci G, Holland KB, Radmacher MD, Maharry K, Paschka P, Whitman SP, Mrózek K, Baldus CD, Vij R, Powell BL, Carroll AJ, Kolitz JE, Caligiuri MA, Larson RA, Bloomfield CD (2009) Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 27(19):3198–3204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Argiropoulos B, Humphries RK (2007) HOX genes in hematopoiesis and leukemogenesis. Oncogene 26(47):6766–6776

    Article  CAS  PubMed  Google Scholar 

  20. Tonks A, Hills R, White P, Rosie B, Mills KI, Burnett AK, Darley RL (2007) CD200 as a prognostic factor in acute myeloid leukaemia [letter]. Leukemia 21(3):566–568

    Article  CAS  PubMed  Google Scholar 

  21. Kim JG, Sohn SK, Kim DH, Baek JH, Lee NY, Suh JS, Chae SC, Lee KS, Lee KB (2005) Clinical implications of angiogenic factors in patients with acute or chronic leukemia: hepatocyte growth factor levels have prognostic impact, especially in patients with acute myeloid leukemia. Leuk Lymphoma 46(6):885–891

    Article  PubMed  Google Scholar 

  22. Toren A, Bielorai B, Jacob-Hirsch J, Fisher T, Kreiser D, Moran O, Zeligson S, Givol D, Yitzhaky A, Itskovitz-Eldor J, Kventsel I, Rosenthal E, Amariglio N, Rechavi G (2005) CD133-positive hematopoietic stem cell “stemness” genes contain many genes mutated or abnormally expressed in leukemia. Stem Cells 23(8):1142–1153

    Article  CAS  PubMed  Google Scholar 

  23. Sekeres MA, Elson P, Kalaycio ME, Advani AS, Copelan EA, Faderl S, Kantarjian HM, Estey E (2009) Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients. Blood 113:28–36

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Hovland R, Rosenquist R, Ommen H, Abrahamsson J, Forestier E, Jahnukainen K (2011) Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. Blood 118:5905–5913

    Article  PubMed  Google Scholar 

  25. Eid MA, Attia M, Abdou S, El-Shazly SF, Elahwal L, Farrag W, Mahmoud L (2010) BAALC and ERG expression in acute myeloid leukemia with normal karyotype: impact on prognosis. Int J Lab Hematol 32(2):197–205

    Article  CAS  PubMed  Google Scholar 

  26. Krstovski N, Tosic N, Janic D, Dokmanovic L, Kuzmanovic M, Spasovski V, Pavlovic S (2010) Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature. Med Oncol 27(3):640–645

    Article  CAS  PubMed  Google Scholar 

  27. Tanner ST, Austin JL, Leone G, Rush LJ, Plass C, Heinonen K, Mrózek K, Sill H, Knuutila S, Kolitz JE, Archer KJ, Caligiuri MA, Bloomfield CD, de la Chapelle A (2001) BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. PNAS 98(24):13901–13906

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Baldus CD, Tanner SM, Ruppert AS et al (2003) BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B study. Blood 102(5):1613–1618

    Article  CAS  PubMed  Google Scholar 

  29. Haferlach C, Kern W, Schindela S, Kohlmann A, Alpermann T, Schnittger S, Haferlach T (2012) Gene expression of BAALC, CDKN1B, ERG, and MN1 adds independent prognostic information to cytogenetics and molecular mutations in adult acute myeloid leukemia. Genes Chromosom Cancer 51:257–265

    Article  CAS  PubMed  Google Scholar 

  30. Hermkens MC, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Baruchel A, Stary J, Reinhardt D, Zimmerman M, de Haas V, Pieters R, Zwaan CM (2013) The clinical relevance of BAALC and ERG expression levels in pediatric AML. Leukemia 27:735–737

    Article  CAS  PubMed  Google Scholar 

  31. Schwind S, Marcucci G, Maharry K, Radmacher M, Mrózek K, Holland K et al (2010) BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood 116(25):5660–5669

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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The authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Hematology Unit, Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura Cancer Institute, Mansoura, Egypt

    Salah Aref, Amre El Sadiek & Nadia El Menshawy

  2. Medical Oncology Unit, Mansoura Faculty of Medicine, Mansoura Cancer Institute, Mansoura, Egypt

    Tawfik Al Khodary

  3. Clinical Hematology Unit, Mansoura Faculty of Medicine, Mansoura Cancer Institute, Mansoura, Egypt

    Tarek Abou Zeed

  4. Pediatric Oncology Unit, Mansoura Faculty of Medicine, Mansoura Cancer Institute, Mansoura, Egypt

    Rasha Al Ashery

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  1. Salah Aref
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Correspondence to Salah Aref.

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Aref, S., Al Khodary, T., Zeed, T.A. et al. The Prognostic Relevance of BAALC and ERG Expression Levels in Cytogenetically Normal Pediatric Acute Myeloid Leukemia. Indian J Hematol Blood Transfus 31, 21–28 (2015). https://doi.org/10.1007/s12288-014-0395-z

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  • DOI: https://doi.org/10.1007/s12288-014-0395-z

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