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Open Access 01-12-2013 | Research

A standardized microarray assay for the independent gene expression markers in AML: EVI1 and BAALC

Authors: Jaap Brand, Martin H van Vliet, Leonie de Best, Peter JM Valk, Henk E Viëtor, Bob Löwenberg, Erik H van Beers

Published in: Experimental Hematology & Oncology | Issue 1/2013

Abstract

High levels of BAALC, ERG, EVI1 and MN1 expression have been associated with shorter overall survival in AML but standardized and clinically validated assays are lacking. We have therefore developed and optimized an assay for standardized detection of these prognostic genes for patients with intermediate cytogenetic risk AML. In a training set of 147 intermediate cytogenetic risk cases we performed cross validations at 5 percentile steps of expression level and observed a bimodal significance profile for BAALC expression level and unimodal significance profiles for ERG and MN1 levels with no statistically significant cutoff points near the median expression level of BAALC, ERG or MN1. Of the possible cutoff points for expression levels of BAALC, ERG and MN1, just the 30th and 75th percentile of BAALC expression level and the 30th percentile of MN1 expression level cutoff points showed clinical significance. Of these only the 30th percentile of BAALC expression level reproduced in an independent verification (extended training) data set of 242 cytogenetically normal AML cases and successfully validated in an external cohort of 215 intermediate cytogenetic risk AML cases. Finally, we show independent prognostic value for high EVI1 and low BAALC in multivariate analysis with other clinically relevant molecular AML markers. We have developed a highly standardized molecular assay for the independent gene expression markers EVI1 and BAALC.

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Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G, Caligiuri MA, Carroll AJ, Vardiman JW, Powell BL, Allen SL, Moore JO, Larson RA, Kolitz JE, Chapelle A, Bloomfield CD: BAALC expression predicts clinical outcome of de novo acute myeloid leukaemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood 2003, 102: 1613–1618. 10.1182/blood-2003-02-0359PubMedCrossRef

Baldus CD, Thiede C, Soucek S, Bloomfield CD, Thiel E, Ehninger G: BAALC Expression and FLT3 Internal Tandem Duplication Mutations in Acute Myeloid Leukemia Patients With Normal Cytogenetics: Prognostic Implications. J Clin Oncol 2006, 24: 790–797. 10.1200/JCO.2005.01.6253PubMedCrossRef

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: 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 2009, 27: 5031–5038. 10.1200/JCO.2008.20.5328PubMedCrossRef

Langer C, Radmacher MD, Ruppert AS, Whitman SP, Paschka P, Mrózek K, Baldus CD, Vukosavljevic T, Liu CG, Ross ME, Powell BL, de la Chapelle A, Kolitz JE, Larson RA, Marcucci G, Bloomfield CD: High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. Blood 2008, 111: 5371–5379. 10.1182/blood-2007-11-124958PubMedCentralPubMedCrossRef

Santamaría C, Chillón MC, García-Sanz R, Pérez C, Caballero MD, Mateos MV, Ramos F, García de Coca A, Alonso JM, Giraldo P, Bernal T, Queizán JA, Rodríguez JN, Puig N, Balanzategui A, Sarasquete ME, Alcoceba M, Díaz-Mediavilla J, San Miguel J, González M: BAALC is an important predictor of refractoriness to chemotherapy and poor survival in intermediate-risk acute myeloid leukemia (AML). Ann Hematol 2010, 89: 453–458. 10.1007/s00277-009-0864-xPubMedCrossRef

Marcucci G, Baldus CD, Ruppert AS, Radmacher MD, Mrózek K, Whitman SP, Kolitz JE, Edwards CG, Vardiman JW, Powell BL, Baer MR, Moore JO, Perrotti D, Caligiuri MA, Carroll AJ, Larson RA, de la Chapelle A, Bloomfield CD: Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. J Clin Oncol 2005, 23: 9234–9242. 10.1200/JCO.2005.03.6137PubMedCrossRef

Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C, Mrózek K, Baldus CD, Carroll AJ, Powell BL, Bloomfield CD: 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 2007, 22: 3337–3343.CrossRef

Heuser M, Beutel G, Krauter J, Döhner K, von Neuhoff N, Schlegelberger B, Ganser A: High meningioma 1 ( MN1 ) expression as a predictor for poor outcome in acute myeloid leukaemia with normal cytogenetics. Blood 2006, 108: 3898–3905. 10.1182/blood-2006-04-014845PubMedCrossRef

Schwind S, Marcucci G, Kohlschmidt J, Radmacher MD, Mrózek K, Maharry K, Becker H, Metzeler KH, Whitman SP, Wu YZ, Powell BL, Baer MR, Kolitz JE, Carroll AJ, Larson RA, Caligiuri MA, Bloomfield CD: Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia. Blood 2011, 118: 4188–4198. 10.1182/blood-2011-06-357764PubMedCentralPubMedCrossRef

10.

Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S, Hack R, Slater R, Smit EM, Beverloo HB, Verhoef G, Verdonck LF, Ossenkoppele GJ, Sonneveld P, de Greef GE, Löwenberg B, Delwel R: High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 2003, 101: 837–845. 10.1182/blood-2002-05-1459PubMedCrossRef

11.

Lughthart S, van Drunen E, van Norden Y, van Hoven A, Erpelinck CA, Valk PJ, Beverloo HB, Löwenberg B, Delwel HR: High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood 2008, 111: 4329–4337. 10.1182/blood-2007-10-119230CrossRef

12.

Gröschel S, Lugthart S, Schlenk RF, Valk PJ, Eiwen K, Goudswaard C, van Putten WJ, Kayser S, Verdonck LF, Lübbert M, Ossenkoppele GJ, Germing U, Schmidt-Wolf I, Schlegelberger B, Krauter J, Ganser A, Döhner H, Löwenberg B, Döhner K, Delwel R: High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. J Clin Oncol 2010, 28: 2101–2107. 10.1200/JCO.2009.26.0646PubMedCrossRef

13.

Balgobind BV, Lugthart S, Hollink IH, Arentsen-Peters ST, van Wering ER, de Graaf SS, Reinhardt D, Creutzig U, Kaspers GJ, de Bont ES, Stary J, Trka J, Zimmermann M, Beverloo HB, Pieters R, Delwel R, Zwaan CM, van den Heuvel-Eibrink MM: EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia. Leukemia 2010, 24: 942–949. 10.1038/leu.2010.47PubMedCrossRef

14.

Bienz M, Ludwig M, Mueller BU, Oppliger Leibundgut E, Ratschiller D, Solenthaler M, Fey MF, Pabst T: Risk Assessment in Patients with Acute Myeloid Leukemia and a Normal Karyotype. Clin Cancer Res 2005, 11: 1416–1424. 10.1158/1078-0432.CCR-04-1552PubMedCrossRef

15.

Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF, Vellenga E, De Greef GE, Jacky E, Van der Lelie J, Boogaerts MA, Löwenberg B: Prognostic Index for Adult Patients With Acute Myeloid Leukemia in First Relapse. J Clin Oncol 2005, 23: 1969–1978. 10.1200/JCO.2005.06.027PubMedCrossRef

16.

Rockova V, Abbas S, Wouters BJ, Erpelinck CA, Beverloo HB, Delwel R, van Putten WL, Löwenberg B, Valk PJ: Risk-stratification of intermediate-risk analysis of a multitude of gene mutation and gene expression markers. Blood 2011, 118: 1068–1076.CrossRef

17.

Grossmann V, Schnittger S, Kohlmann A, Eder C, Roller A, Dicker F, Schmid C, Wendtner CM, Staib P, Serve H, Kreuzer KA, Kern W, Haferlach T, Haferlach C: A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood 2012, 120: 2963–2972. 10.1182/blood-2012-03-419622PubMedCrossRef

18.

Gregory TK, Wald D, Chen Y, Vermaat JM, Xiong Y, Tse W: Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics. J Hematol Oncol 2009, 2: 23. 10.1186/1756-8722-2-23PubMedCentralPubMedCrossRef

19.

Santamaría CM, Chillón MC, García-Sanz R, Pérez C, Caballero MD, Ramos F, de Coca AG, Alonso JM, Giraldo P, Bernal T, Queizán JA, Rodriguez JN, Fernández-Abellán P, Bárez A, Peñarrubia MJ, Balanzategui A, Vidriales MB, Sarasquete ME, Alcoceba M, Díaz-Mediavilla J, San Miguel JF, Gonzalez M: Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia. Blood 2009, 114: 148–152. 10.1182/blood-2008-11-187724PubMedCrossRef

20.

Haferlach C, Kern W, Schindela S, Kohlmann A, Alpermann T, Schnittger S, Haferlach T: Gene expression of BAALC, CDKN1B, ERG, and MN1 adds independent prognostic information to cytogenetics and molecular mutations in adult acute myeloid leukemia. Genes Chromosomes Cancer 2012, 51: 257–265. 10.1002/gcc.20950PubMedCrossRef

21.

Metzeler KH, Hummel M, Bloomfield CD, Spiekermann K, Braess J, Sauerland MC, Heinecke A, Radmacher M, Marcucci G, Whitman SP, Maharry K, Paschka P, Larson RA, Berdel WE, Büchner T, Wörmann B, Mansmann U, Hiddemann W, Bohlander SK, Buske C, Cancer and Leukemia Group B: An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood 2008, 112: 4193–4201. 10.1182/blood-2008-02-134411PubMedCentralPubMedCrossRef

22.

Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van doorn-Khosrovani S, Boer JM, Beverloo HB, Moorhouse MJ, van der Spek PJ, Löwenberg B, Delwel R: Prognostically Useful Gene-Expression Profiles in Acute Myeloid Leukemia. N Engl J Med 2004, 350: 1617–1628. 10.1056/NEJMoa040465PubMedCrossRef

Title: A standardized microarray assay for the independent gene expression markers in AML: EVI1 and BAALC
Authors: Jaap Brand
Martin H van Vliet
Leonie de Best
Peter JM Valk
Henk E Viëtor
Bob Löwenberg
Erik H van Beers
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Experimental Hematology & Oncology / Issue 1/2013
Electronic ISSN: 2162-3619
DOI: https://doi.org/10.1186/2162-3619-2-7

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