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Acute Myeloid Leukemia with Biallelic CEBPA Gene Mutations and Normal Karyotype Represents a Distinct Genetic Entity Associated

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Acute Myeloid Leukemia with Biallelic CEBPA Gene Mutations and Normal Karyotype Represents a Distinct Genetic Entity Associated VOLUME 28 ⅐ NUMBER 4 ⅐ FEBRUARY 1 2010 JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT Acute Myeloid Leukemia With Biallelic CEBPA Gene Mutations and Normal Karyotype Represents a Distinct Genetic Entity Associated With a Favorable Clinical Outcome Annika Dufour, Friederike Schneider, Klaus H. Metzeler, Eva Hoster, Stephanie Schneider, Evelyn Zellmeier, Tobias Benthaus, Maria-Cristina Sauerland, Wolfgang E. Berdel, Thomas Bu¨chner, Bernhard Wo¨rmann, Jan Braess, Wolfgang Hiddemann, Stefan K. Bohlander, and Karsten Spiekermann See accompanying article on page 578 From the Laboratory for Leukemia Diag- nostics, Department of Internal Medi- ABSTRACT cine III; Institute for Medical Informatics, Biometry and Epidemiol- Purpose ogy, University of Munich-Grosshadern; CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to Clinical Cooperative Group “Leukemia,” explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal HelmholtzZentrum Mu¨nchen, German (CN) acute myeloid leukemia (AML). Research Center for Environmental Health, Munich; Departments of Medi- Patients and Methods cal Informatics and Biomathematics and Four hundred sixty-seven homogeneously treated patients with CN-AML were subdivided into Medicine A, Hematology and Oncology, moCEBPA,biCEBPA, and wild-type (wt) CEBPA patients. The subgroups were analyzed for clinical University of Mu¨nster, Mu¨nster; and parameters and for additional mutations in the NPM1, FLT3, and MLL genes. Furthermore, we Department of Hematology and Oncol- obtained gene expression profiles using oligonucleotide microarrays. ogy, Municipal Hospital, Braunschweig, Germany. Results Only patients with biCEBPA had an improved median overall survival when compared with Submitted December 22, 2008; ϭ accepted June 4, 2009; published patients with wtCEBPA (not reached v 20.4 months, respectively; P .018), whereas patients online ahead of print at www.jco.org on with moCEBPA (20.9 months) and wtCEBPA had a similar outcome (P ϭ .506). Multivariable December 28, 2009. analysis confirmed biCEBPA, but not moCEBPA, mutations as an independent favorable prognos- Written on behalf of the German Acute tic factor. Interestingly, biCEBPA mutations, compared with wtCEBPA, were never associated Myeloid Leukemia Cooperative Group. with mutated NPM1 (0% v 43%, respectively; P Ͻ .001) and rarely associated with FLT3 internal ϭ Supported in part by National Genome tandem duplication (ITD; 5% v 23%, respectively; P .059), whereas patients with moCEBPA had Network Plus Grant No. 01GS0448 a similar frequency of mutated NPM1 and a significantly higher association with FLT3-ITD (S.K.B., Bundesministerium fu¨r Bildung compared with patients with wtCEBPA (44% v 23%, respectively; P ϭ .037). Furthermore, und Forschung); and by Deutsche patients with biCEBPA showed a homogeneous gene expression profile that was characterized by Forschungsgemeinschaft Grant SFB downregulation of HOX genes, whereas patients with moCEBPA showed greater heterogeneity in 684/A 12 (K.S). their gene expression profiles. Both A.D. and F.S. contributed equally to this work. Conclusion Biallelic disruption of the N and C terminus of CEBPA is required for the favorable clinical outcome Authors’ disclosures of potential con- of CEBPA-mutated patients and represents a distinct molecular subtype of CN-AML with a flicts of interest and author contribu- different frequency of associated gene mutations. These findings are of great significance for tions are found at the end of this article. risk-adapted therapeutic strategies in AML. Corresponding author: Karsten Spiekermann, MD, Department of Inter- J Clin Oncol 28:570-577. © 2009 by American Society of Clinical Oncology nal Medicine III, University Hospital Großhadern, Ludwig-Maximilians University, Campus Großhadern, (PTD) of the MLL gene are the most common prog- INTRODUCTION 1 Marchioninistr 15, 81377 Mu¨nchen, nostic markers. Accordingly, the recently revised Germany; e-mail: karsten.spiekermann@ fourth edition of the WHO Classification of Tumours med.uni-muenchen.de. Cytogenetically normal (CN) acute myeloid leuke- of the Haematopoietic and Lymphoid Tissues strongly © 2009 by American Society of Clinical mia (AML) represents a molecularly heterogeneous recommends a routine mutational screen of NPM1, Oncology disease entity in which mutations in certain genes CEBPA, and FLT3-ITD and includes AML with mu- 0732-183X/10/2804-570/$20.00 have been linked to clinical outcome. Mutations in tated NPM1 and AML with mutated CEBPA as pro- DOI: 10.1200/JCO.2008.21.6010 the CEBPA and NPM1 genes, internal tandem du- visional entities.2 plications (ITD) of the fms-like tyrosine kinase 3 The CEBPA gene located on chromosome 19 (FLT3) gene, and partial tandem duplications band q13.1 encodes a member of the basic region 570 © 2009 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on March 18, 2016. For personal use only. No other uses without permission. Copyright © 2010 American Society of Clinical Oncology. All rights reserved. Characterization of Biallelic CEBPA-Mutated AML leucine zipper (bZIP) transcription factor family, which coordinates proteins with disrupted homo- and heterodimerization domains and myeloid differentiation and cellular growth arrest.3 We and others consequently impaired DNA binding activities.8,9 have reported CEBPA mutations in 8% to 19% of patients with CN- Most CEBPA-mutated patients with AML carry two mutations AML.1,4-7 The mutations are typically associated with CN-AML,7,8 on separate alleles of CEBPA with a specific combination of an French-American-British AML subtypes M1 or M2, and a better over- N-terminal frameshift mutation on one allele and a C-terminal in- all survival (OS).1,5,6 CEBPA mutations have largely been divided into frame mutation on the other allele.10 Furthermore, AML blasts from the following two main categories: N-terminal frameshift mutations patients with biallelic CEBPA mutations (biCEBPA) have been asso- that specifically abolish the translation of the full-length (42-kDa) ciated with a distinct immunophenotype.11 Therefore, we wanted to CEBPA protein (p42 CEBPA), leading to the overexpression of a investigate, in a large and homogeneously treated cohort of patients shorter, dominant negative 30-kDa isoform of CEBPA (p30 CEBPA).7 with CN-AML, whether patients with biCEBPA form a clinically and C-terminal in-frame mutations in the bZIP domain of CEBPA lead to molecularly distinct group that can be separated from patients with Table 1. Patient Demographics and Clinical and Molecular Characteristics of CN-AML Patients According to the Number of Mutated Alleles in CEBPA wtCEBPA (n ϭ 429) moCEBPA (n ϭ 18) biCEBPA (n ϭ 20) ء Characteristic No. of Patients % No. of Patients % No. of Patients % P Age, years .693 Median 61 65 62 Range 17-85 18-78 28-75 Female 192† 45 15 83 9† 45 .006 FAB type (n ϭ 447) .335 M0 16 4 0 0 0 0 M1 83 20 5 28 6 30 M2 162 40 9 50 12 60 M3 000000 M4 90 22 3 17 1 5 M5 37 9 0 0 0 0 M6 21 5 1 6 1 5 M1/M2 (n ϭ 447) 245 60 14 78 18† 90 .009 Type of disease (n ϭ 466) .613 De novo AML 332 78 14 78 19 95 AML from MDS 67 16 3 17 1 5 Therapy-related AML 14 3 1 6 0 0 High-risk MDS‡ 15 4 0 0 0 0 Allogeneic stem-cell transplantation 89 21 4 22 5 25 .893 Hemoglobin, g/L (n ϭ 457) .035 Median 93 94 103† Range 47-164 72-131 86-125 WBC count, ϫ109/L (n ϭ 460) .158 Median 9.6 19.0 10.5 Range 0.5-170.0 1.7-128.9 0.9-103.5 Platelet count, ϫ109/L, n ϭ 460 .303 Median 58 50 40 Range 3-643 10-223 18-176 Bone marrow blasts, % (n ϭ 439) .118 Median 75 85 80 Range 10-100 20-97 30-95 LDH, U/L (n ϭ 458) .378 Median 372 398 284 Range 8-14,332 152-2,660 205-1,238 Mutated NPM1 (n ϭ 413) 162/375§ 43 8 41 0† 0 .001 FLT3-ITD (n ϭ 447) 94/409† 23 8 44 1† 5 .014 FLT3-TKD (n ϭ 379) 24/346 7 1/15 7 0/18 0 .720 MLL-PTD (n ϭ 426) 34/391 9 1/17 6 0/18 0 .611 Abbreviations: CN-AML, cytogenetically normal acute myeloid leukemia; wtCEBPA, wild-type CEBPA;moCEBPA, monoallelic CEBPA mutation; biCEBPA, biallelic CEBPA mutations; FAB, French-American-British; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; LDH, lactate dehydrogenase; NPM1, nucleophosmin; FLT3-ITD, internal tandem duplication of the FLT3 gene; FLT3-TKD, tyrosine kinase domain mutations; MLL-PTD, partial tandem duplication of the MLL gene. .Differences between wtCEBPA,moCEBPA, and biCEBPA were calculated using the Kruskal-Wallis test or ␹2 test/Fisher’s exact testء †Statistically significant also in pairwise comparison to moCEBPA applying the Mann-Whitney U test or ␹2 test/Fisher’s exact test. ‡Blasts ϭ 10% to 20%. §No./total No. with available data. www.jco.org © 2009 by American Society of Clinical Oncology 571 Downloaded from jco.ascopubs.org on March 18, 2016. For personal use only. No other uses without permission. Copyright © 2010 American Society of Clinical Oncology. All rights reserved. Dufour et al monoallelic CEBPA mutations (moCEBPA). We show here that bial- lelic, but not monoallelic, disruption of CEBPA is required for a A All patients 100 favorable outcome and that these patients represent a distinct molec- (N = 467) ular subgroup within AML with mutated CEBPA with a characteristic gene expression profile. 80 biCEBPA (n = 20) P = .018 PATIENTS AND METHODS 60 moCEBPA (n = 18) P = .506 Patients 40 In this analysis, we included diagnostic bone marrow or peripheral- blood samples from 467 adults with a normal karyotype and with a median age Overall Survival (%) of 61 years who were enrolled onto the German Acute Myeloid Leukemia 20 wtCEBPA (n = 429) Cooperative Group (AML CG) 1999 multicenter treatment trial.12 Details regarding patients, patient selection, and treatment regimens are described in the Appendix and in Appendix Table A1 (online only).
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