Originally published as JCO Early Release 10.1200/JCO.2004.06.060 on January 15 2004

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CEBPA Mutations in Younger Adults With Acute Myeloid Leukemia and Normal Cytogenetics: Prognostic Relevance and Analysis of Cooperating Mutations

From the Department of Internal Medicine III, University Hospital of Ulm, Ulm; and Central Unit Biostatistics, German Cancer Research Center, Heidelberg, Germany

Address reprint requests to Hartmut Döhner, MD, Department of Internal Medicine III, University Hospital of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany; e-mail: hartmut.doehner{at}medizin.uni-ulm.de

	ABSTRACT

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PURPOSE: To assess the prognostic relevance of mutations in the CEBPA gene encoding CCAAT/enhancer binding protein alpha (C/EBP) in a large prospective series of younger adults with acute myeloid leukemia (AML) and normal cytogenetics.

PATIENTS AND METHODS: The entire CEBPA coding region was sequenced in diagnostic samples from 236 AML patients 16 to 60 years of age with normal cytogenetics who were uniformly treated on two consecutive protocols of the AML Study Group Ulm, and CEBPA mutation status was correlated with clinical outcome.

RESULTS: CEBPA mutations were detected in 36 (15%) of 236 patients. Twenty-one (9%) of 236 patients had mutations predicted to result in loss of C/EBP function. Remission duration and overall survival (OS) were significantly longer for the 36 patients with CEBPA mutations (P = .01 and P = .05, respectively). On multivariate analysis, wild-type CEBPA was an independent prognostic marker affecting remission duration (hazard ratio, 2.85; P = .01) and OS (hazard ratio, 1.87; P = .04). Analysis of cooperating mutations (both types of activating FLT3 mutations and MLL partial tandem duplications) showed that FLT3 mutations had no significant prognostic influence in patients with CEBPA mutations. Furthermore, there was no significant overlap between the subgroup of patients with CEBPA mutation with predicted loss of C/EBP function and patients with FLT3 or MLL mutations, suggesting that CEBPA loss-of-function mutations define a distinct biologic subclass of AML with normal cytogenetics.

CONCLUSION: Mutant CEBPA predicts favorable prognosis and may improve risk stratification in AML patients with normal cytogenetics.

	INTRODUCTION

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Karyotype at diagnosis provides the most important prognostic information in adult acute myeloid leukemia (AML) [1-5]. By conventional cytogenetic analysis, approximately 50% of patients lack clonal chromosome aberrations [4], and discriminating between prognostically different subsets of patients within this intermediate-risk group by using molecular genetic approaches is a major challenge [6-11].

CCAAT/enhancer binding protein alpha (C/EBP) is a transcription factor involved in the regulation of myelopoiesis [12-14]. C/EBP expression occurs predominantly in myelomonocytic cells and is specifically upregulated during granulocyte differentiation [15-17]. Conditional expression of C/EBP induces granulocytic development of bipotential myeloid progenitors [15], and transient transfection studies have shown that C/EBP regulates the promoters of a number of granulocyte-specific genes [18-22]. The activity of C/EBP to induce granulocyte differentiation is enhanced by RAS-mediated phosphorylation of serine 248 of the C/EBP transactivation domain [23].

Like other members of the basic region leucine zipper (bZIP) class of transcription factors, C/EBP consists of highly homologous C-terminal DNA-binding (basic region) and dimerization (leucine zipper) motifs and two less-conserved N-terminal transactivation domains [24,25]. The CEBPA gene maps to chromosome band 19q13.1 and has a GC-rich (more than 70%) coding region that is contained within a single exon [26].

On the basis of the observation that C/EBP-deficient mice lack mature granulocytes [27], it has been speculated that CEBPA mutations might contribute to the differentiation block specific to AML. In support of this hypothesis, CEBPA mutations were identified in approximately 7% of AML patients [28,29]. These mutations resulted in elimination of upstream initiation sites and increased expression of truncated C/EBP proteins with dominant-negative properties (N-terminal nonsense mutations) or in C/EBP mutants with decreased DNA-binding potential (C-terminal in-frame deletions, insertions, or duplications). The frequency of CEBPA mutations was highest in patients with French-American-British (FAB) subtype M2, and the majority of patients with mutations had normal cytogenetics. In AML patients with t(8;21)(q22;q22), which is strongly associated with M2 morphology, the resulting AML1-ETO fusion protein abrogates C/EBP function by downregulating CEBPA expression to levels insufficient for granulocyte differentiation [30]. These data and the finding that the differentiation block observed in Cebpa knockout mice resembles the M2 phenotype [27] suggest that CEBPA mutations and the t(8;21) may act via a common pathway (inhibition of C/EBP function) in the pathogenesis of AML.

To date, two studies focusing on the prognostic impact of CEBPA mutations in AML have been published. Preudhomme et al [31] examined pretreatment samples from 135 adults who had been entered into a treatment trial of the Acute Leukemia French Association. Different types of mutations were identified in 15 (16%) of 91 patients with intermediate-risk cytogenetics, as defined according to the criteria proposed by the British Medical Research Council [3], and the presence of a CEBPA mutation was associated with significantly better clinical outcome. In a study from the Netherlands, 277 patients were screened for mutations in the bZIP domain. In-frame insertions were identified in 12 patients (4%; eight patients with normal cytogenetics and four patients with other chromosome abnormalities) and were subsequently shown to coincide with N-terminal mutations on the other allele. Among the 187 patients with intermediate-risk karyotypes, patients with the mutations had significantly increased event-free survival and overall survival (OS) [32].

There is evidence that mutations in hematopoietic transcription factors, resulting in impaired differentiation, cooperate with mutations in hematopoietic tyrosine kinases (TKs), which confer a proliferative or survival advantage, or both, giving rise to the AML phenotype [33]. Studies in mice demonstrated that the AML1-ETO and CBFß-MYH11 fusion genes, resulting from t(8;21) and inv(16), can block myeloid differentiation but are not sufficient to cause overt leukemia [34-37]. These observations led to the assumption that additional genetic events are required for the development of an AML phenotype. In support of this hypothesis, TKs have been found to be mutationally activated in some AML patients with t(8;21) or inv(16) [7-9,38,39]. The most commonly mutated TK is FMS-like tyrosine kinase 3 (FLT3), which is mutationally activated in approximately 30% of adult AML patients. However, although FLT3 mutations may be associated with any of the major classes of cytogenetic abnormalities, including those targeting the core-binding factor transcription-factor complex [ie, t(8;21) and inv(16)], they are most often associated with normal cytogenetics [7-9,40]. Whether in such cases FLT3 mutations are complemented by mutations in transcription-factor genes (for example, CEBPA) not frequently involved in gross cytogenetic changes remains to be determined.

The objective of this study was to assess the prognostic relevance of CEBPA mutations in a homogeneous group of young adults with AML and normal cytogenetics who were uniformly treated using two consecutive protocols of the AML Study Group Ulm. In a search for cooperating mutations and to provide a meaningful multivariate analysis, all patients were also analyzed for the presence of activating FLT3 mutations and partial tandem duplications (PTDs) of the mixed-lineage leukemia gene (MLL PTDs).

	PATIENTS AND METHODS

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Patients
Diagnostic bone marrow (BM) or peripheral-blood (PB) samples were available from 236 patients 16 to 60 years of age with AML diagnosed according to FAB Cooperative Group criteria [41] and normal cytogenetics who had been entered onto the multicenter treatment trials AML HD93 (72 patients; August 1993 to January 1998) [42] and AML HD98-A (164 patients; February 1998 to April 2002) of the AML Study Group ULM. AML HD93 enrolled patients with de novo AML and patients with secondary AML after a primary malignancy. The ongoing AML HD98-A trial also includes patients with refractory anemia with excess blasts in transformation and patients with AML after myelodysplastic syndrome. For this molecular study, the only criterion used to include patients was the availability of a BM or PB sample from diagnosis for mutation analysis of the CEBPA gene. Approval was obtained from the institutional review boards of the participating institutions. All patients gave informed consent for both treatment and cryopreservation of BM and PB according to the Declaration of Helsinki.

Therapy of Patients With Normal Cytogenetics
All patients entered onto AML HD93 and AML HD98-A received intensive, response-adapted double-induction and consolidation therapy. Double-induction therapy consisted of a course of idarubicin 12 mg/m² on days 1, 3, and 5; cytarabine 100 mg/m² continuously on days 1 through 7; and etoposide 100 mg/m² on days 1 through 3 (ICE), followed by a second course of ICE started between days 21 and 28 in patients with a response to the first course. The alternative therapy was a course of cytarabine 3 g/m² every 12 hours on days 1 through 3 plus mitoxantrone 12 mg/m² on days 2 and 3 (HAM) in patients with ICE-refractory disease. First consolidation therapy consisted of a course of HAM.

Second consolidation therapy of patients with normal cytogenetics differed between the two trials: in the AML HD93 trial, patients 16 to 54 years of age were assigned to a course according to the sequential HAM protocol (cytarabine 3 g/m² every 12 hours on days 1, 2, 8, and 9; mitoxantrone 10 mg/m² on days 3, 4, 10, and 11); patients 55 to 60 years of age received the less-intensive HAM regimen. In the AML HD98-A trial, patients were randomly assigned to a second course of HAM or myeloablative therapy (total-body irradiation and cyclophosphamide or busulfan plus cyclophosphamide), followed by autologous stem-cell transplantation. In both trials, patients were assigned to receive allogeneic stem-cell transplantation if an HLA-compatible donor was available.

Cytogenetic and Molecular Genetic Analysis
All patients were studied centrally by chromosome-banding analysis using standard techniques. Karyotypes were described according to the International System for Cytogenetic Nomenclature [43]. To improve the accuracy of cytogenetic diagnosis, all specimens were also analyzed by fluorescence in situ hybridization using a comprehensive DNA probe set for the detection of the most relevant AML-associated genomic aberrations [44,45]. In addition, all patients were analyzed for mutations in the FLT3 and MLL genes (FLT3, internal tandem duplications [ITDs] and activation-loop mutations at D835; MLL, PTDs) [6,7].

Analysis of CEBPA Coding Region Sequence Variations
Genomic DNA was isolated from mononuclear cell preparations stored at -70°C using the DNAzol reagent (GibcoBRL, Eggenstein, Germany). Four overlapping primer pairs were used to amplify the entire CEBPA coding region including 92 nucleotides of the 5'-untranslated region and 58 nucleotides of the 3'-untranslated region. The positions of the primers complementary to the CEBPA cDNA sequence (GenBank accession number U34070) were 1F (500 to 519) 5'-GGCGAGCAGGGTCTCCGGGT-3', 1R (824 to 844) 5'-TGTGCTGGAACAGGTCGGCCA-3', 2F (744 to 761) 5'-GCTGGGCGGCATCTGCGA-3', 2R (1026 to 1045) 5'-CCCCGACGCGCTCGTACAGG3', 3F (998 to 1017) 5'-CCGGCTACCTGGACGGCAGG-3', 3R (1414 to 1441) 5'-CGTTGCTGTTCTTGTCCACCGACTTCTT-3', 4F (1312 to 1328) 5'-CTCGGTGCCGCCGGCCT-3', and 4R (1706 to 1726) 5'-AACCACTCCCTGGGTCCCCGC-3'.

The total reaction volume of 50 µL contained 500 ng DNA (1 µg for primer pair 3), 10 pmol of each primer, deoxynucleotide triphosphates (10 mmol/L each), 2.5 U Taq polymerase, a polymerase chain reaction (PCR) additive facilitating amplification of GC-rich templates, and supplied buffer (Qiagen, Hilden, Germany). Samples were amplified using the following PCR conditions: 95°C for 15 minutes; 35 cycles of 95°C for 1 minute, 68°C for 3 minutes; and 68°C for 3 minutes. PCR products were sequenced in both directions with primers 1F/1R, 2F/2R, 3F/3R, and 4F/4R using the ABI Ready Reaction Dye Terminator Cycle Sequencing Kit (Applied Biosystems, Darmstadt, Germany).

In samples with a CEBPA coding region sequence variation, abnormal PCR products were cloned into the pCR4-TOPO vector (Invitrogen, Groningen, the Netherlands). Twelve recombinant colonies were cultured in Luria-Bertani medium, and plasmid DNA was prepared using the Plasmid Mini Kit (Qiagen). Cloned fragments were sequenced with the primers used to amplify the corresponding CEBPA regions from genomic DNA.

To determine whether patients with sequence variations in different regions of the CEBPA gene had biallelic changes, the entire coding region was amplified with primers 6F and 6R under the previously described PCR conditions and ligated into the pCR4-TOPO cloning vector (Invitrogen). The positions of 6F and 6R complementary to the CEBPA cDNA sequence were 6F (573 to 601) 5'-GGAGAACTCTAACTCCCCCATGGAGTCGG-3' and 6R (1651 to 1670) 5'-CCTCACGCGCAGTTGCCCAT-3'.

Clones were partly sequenced with the primers used to amplify the CEBPA regions from genomic DNA. All sequencing reactions were analyzed on an ABI 310 Prism Sequencer (Applied Biosystems).

Statistical Analyses
Analyses were based on data available as of February 15, 2003. The median follow-up duration was calculated according to the method of Korn [46]. Patient characteristics and complete remission (CR) rate comparisons were performed using the Fisher's exact test for categoric variables and the Wilcoxon rank sum test for continuous variables. The Kaplan-Meier method was used to estimate distributions of remission duration and OS [47]. Differences between two survival distributions were analyzed using the log-rank test [48]. For comparisons among three groups of patients reporting significance at the P = .05 level, pair-wise comparisons were conducted. To assess the significance of pair-wise comparisons, the alpha level was adjusted for multiple tests [49]. The proportional hazards regression model of Cox was used to identify prognostic factors [50]. Possible prognostic factors were age, WBC count, serum lactate dehydrogenase level at diagnosis, CEBPA mutation status, FLT3 mutation status, MLL PTD status, and response to the first course of induction therapy (for remission duration). The study (AML HD93 or AML HD98-A) was incorporated as stratification factor to account for study effects on remission duration and OS. Statistical computations were performed using the software packages SAS (Version 6.12; SAS Institute, Cary, NC) and R (Version 1.6.2) [51].

Criteria for Treatment Outcomes
Response to induction therapy was assessed at two different time points. The first time point was between days 21 and 28 after the first course of induction therapy. Response to the first course of induction therapy was defined as a 50% or greater reduction of BM blasts from pretreatment values. Because the second course of induction therapy was scheduled to start immediately after response assessment, complete hematologic regeneration was not a requirement. The second time point was after double-induction therapy. In accordance with standard criteria [52], CR required less than 5% BM blasts, an absolute neutrophil count of 1.5 x 10⁹/L or more, a platelet count of 100 x 10⁹/L or more, no blasts in the PB, and no extramedullary leukemia. Therapeutic failures were classified as either refractory disease or early or hypoplastic death (death < 7 days after completion of the first course of induction therapy or death during the remainder of double-induction therapy). Relapse was defined as more than 10% blasts in two BM aspirates obtained within 2 weeks or new extramedullary leukemia in patients with previously documented CR. Remission duration end points measured from the date of documented CR were relapse (failure), death in CR (censored), and alive in CR at last follow-up (censored). OS end points measured from the date of study entry were death (failure) and alive at last follow-up (censored).

	RESULTS

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CEBPA Coding Region Polymorphisms
Six silent nucleotide changes that would not affect the predicted amino acid sequence were identified. These polymorphisms were present in 32% (1281G>T), 3% (1164C>T), 1% (993G>A), 0.4% (630C>T), 0.4% (1284C>G), and 0.4% (1347G>T) of the 236 samples.

CEBPA Coding Region Mutations
Thirty-six (15%) of 236 patients demonstrated at least one CEBPA coding region mutation (Table 1), and patients with CEBPA mutation were categorized as follows.

Of the remaining 15 CEBPA-mutated cases, two had a C-terminal in-frame mutation as the sole CEBPA abnormality, and 13 demonstrated other types of CEBPA mutations.

There was a statistically significant difference in the prevalence of FAB subtypes M1 and M2 between patients with N-terminal nonsense mutations (19 of 21 patients; 90%) and patients with other types of CEBPA mutations (four of 15 patients; 27%; P = .0002).

Cooperating Mutations
Patients were analyzed for mutations in the FLT3 and MLL genes (Table 2) [6,7]. FLT3 mutations (ITD or D835 mutation, or both) were significantly less frequent in patients with CEBPA mutations than in patients without the mutation (28% v 49%; P = .01). This difference was attributable to the patients with N-terminal nonsense mutations associated with loss of C/EBP function: only two (10%) of 21 patients with loss-of-function mutations had an FLT3 ITD, as opposed to six (40%) of 15 patients with other types of CEBPA mutations (P = .04). An FLT3-D835 mutation was present in none of the patients with loss-of-function mutations, as compared with two (13%) of 15 patients with other mutation types (P = .16). None of the patients with CEBPA mutations had an MLL PTD.

Remission Duration
The estimated median follow-up duration was 30 months. Median remission duration of patients without CEBPA mutations was 26 months, whereas that of the group with mutations was not reached (the last observed event was at 51 months, with a corresponding probability of continuous CR of 61%). The difference between the distributions of remission duration for patients with and without mutations was statistically significant (P = .01; Fig 1). For patients with CEBPA mutations, presence of any FLT3 mutation (ITD or D835 mutation, or both) had no negative impact on remission duration. In fact, there was a trend toward longer remission duration for patients with mutant FLT3 (P = .07): of the 10 patients with CEBPA mutations and FLT3 mutations (ITDs, n = 8; D835 mutations, n = 2), two who were ITD-positive died less than 7 days after completion of the first course of induction therapy (early death); the remaining eight patients are in continuous CR (10, 13, 17, 19, 23, 33, 79, and 98 months from the date of CR, respectively).

View larger version (16K): [in this window] [in a new window]   Fig 1. Remission duration for young acute myeloid leukemia patients with normal cytogenetics according to CEBPA mutation status. Median remission duration for patients without mutations was 26 months, whereas it was not reached in the group with mutations (P = .01).

OS
OS was significantly longer for patients with CEBPA mutations, as compared with patients with wild-type CEBPA (P = .05; Fig 2). Among the 36 patients with CEBPA mutations, the presence of any FLT3 mutation (ITD or D835 mutation, or both) did not significantly influence OS (P = .71). This was also the case with regard to the effect of the FLT3 ITDs alone (P = .99).

View larger version (16K): [in this window] [in a new window]   Fig 2. Overall survival (OS) for young acute myeloid leukemia patients with normal cytogenetics according to CEBPA mutation status. Median OS for patients without mutations was 19 months, whereas it was not reached in the group with mutations (P = .05).

	DISCUSSION

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Our findings confirm and extend those of the two previous studies on the prognostic relevance of CEBPA mutations in AML. Preudhomme et al [31] reported CEBPA mutations in 15 (11%) of 135 patients from the French Acute Leukemia French Association 9000 trial. All patients with mutations fell into the intermediate cytogenetic risk group according to British Medical Research Council criteria [3], which included a total of 91 patients. Individual karyotypes were not reported. Investigators of the Dutch-Belgian Hematology-Oncology Cooperative Group identified 12 patients with C-terminal CEBPA mutations [32]. Four of these 12 patients had clonal chromosome aberrations [del(9q), n = 2; del(11q), n = 1; del(12p), n = 1]. In a recent cytogenetic study, clinical outcome of patients with del(9q) as the sole abnormality was significantly better than that of patients with normal karyotypes, whereas abn(12p) was associated with poor prognosis [2]. To avoid confounding effects of additional chromosome aberrations, we determined the prognostic value of CEBPA mutations in a large prospective series of patients with normal cytogenetics.

In our study as well as in previous investigations [28,29,31,32], patients with N-terminal nonsense mutations in combination with C-terminal in-frame mutations in the bZIP domain have been observed, and the data from the Dutch-Belgian Hematology-Oncology Cooperative Group study indicate that this pattern is associated with favorable clinical outcome [32]. However, in that study, mutation analysis was restricted to screening for bZIP-domain mutations, complemented by a search for N-terminal mutations only in patients with mutations. In contrast, we have sequenced the entire gene in all of our patients and identified eight additional patients with N-terminal nonsense mutations lacking sequence variations in the bZIP domain.

N-terminal nonsense mutations result in premature termination of the full-length 42-kd protein, formation of a truncated 20-kd protein deficient in DNA binding, and upregulation of the 30-kd C/EBP isoform, generated by use of an alternative initiation codon at amino acid 120 within the same reading frame, which has been shown to inhibit wild-type C/EBP in a dominant-negative fashion [28,29]. Therefore, it is expected that even though patients might have a normal wild-type allele, they would still lose C/EBP function.

To test the hypothesis that the biology of certain AML patients is related to loss of C/EBP function, we defined a group of patients with loss-of-function mutations that included all patients with N-terminal nonsense mutations, irrespective of the presence of an accompanying mutation in the bZIP domain. Loss-of-function mutations, which were present in 21 (9%) of our patients, were strongly associated with FAB subtypes M1 and M2, and there was no significant overlap between the group of patients with loss-of-function mutations and patients with activating FLT3 mutations or MLL PTD-positive patients. These observations suggest that CEBPA loss-of-function mutations may define a distinct biologic subclass of AML with normal cytogenetics.

Considering recent data showing that C/EBP function is affected in two favorable-risk AML subtypes [ie, t(8;21)-positive AML, which downregulates CEBPA mRNA levels by the AML1-ETO fusion protein [30], and t(15;17)-positive acute promyelocytic leukemia, which inhibits C/EBP DNA binding by the PML-RAR fusion protein [56,57], we also looked at the clinical outcome of patients with loss-of-function mutations. Remission duration was longer for this subgroup compared with patients with other mutation types or wild-type CEBPA, supporting the concept that loss of C/EBP function might be responsible for the prognostic effect of CEBPA mutations. However, additional patients need to be studied to establish firmly the prognostic value of different types of CEBPA mutations.

The perception that the outcomes of AML patients with normal cytogenetics vary considerably has incited the search for novel prognostic markers to discriminate favorable-risk from unfavorable-risk patients within this heterogeneous group [6-11,40]. By far, the most common molecular abnormality that has been detected in adult AML with normal cytogenetics is FLT3 ITD, and the presence of this mutation has been associated with poor outcome despite intensive treatment [7-9,11,40]. Given the apparent prognostic value of mutant CEBPA, analysis of a possible interaction between FLT3 ITDs and CEBPA mutations is of particular interest. In the French study, FLT3-ITD positivity, which was present in five (33%) of 15 patients, significantly worsened OS in the group with CEBPA mutations, and the authors proposed to classify patients with CEBPA mutations as having intermediate risk or favorable risk, depending on the presence or absence of an FLT3 ITD [31]. We looked at both types of activating FLT3 mutations (ITDs and D835 mutations) and found no negative prognostic influence among patients with CEBPA mutations. In fact, all remitting patients harboring both a CEBPA mutation and an FLT3 mutation remain in continuous CR. Obviously, larger studies are necessary to determine the relationship between these molecular markers within a hierarchical model.

In summary, we demonstrate that mutant CEBPA predicts favorable prognosis in AML with normal cytogenetics. Our results emphasize further the value of molecular techniques for the dissection of this heterogeneous subgroup of patients, which may ultimately lead to improved risk stratification. Furthermore, we describe a novel subclass of AML with normal cytogenetics characterized by CEBPA loss-of-function mutations. The mechanisms by which mutant CEBPA increases the sensitivity of AML to antileukemic treatment, thereby improving clinical outcome, as well as cooperating molecular events in leukemogenesis [58], remain to be determined in future studies.

	Appendix

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The following AMLSG ULM institutions and investigators participated in this study: Universitätsklinikum Bonn, Germany, A. Glasmacher; Universitätsklinikum Düsseldorf, Germany, U. Germing; Universitätsklinikum Giessen, Germany, H. Pralle; Universitätsklinikum Göttingen, Germany, D. Haase; Allgemeines Krankenhaus Altona, Hamburg, Germany, H. Salwender; Universitätskliniken des Saarlandes, Homburg, Germany, F. Hartmann; Universitätsklinikum Innsbruck, Austria, G. Gastl; Städtisches Klinikum Karlsruhe, Germany, J. T. Fischer; Universitätsklinikum Kiel, Germany, M. Kneba; Klinikum rechts der Isar der Technischen Universität München, Germany, K. Götze; Städtisches Krankenhaus München-Schwabing, Germany, C. Waterhouse; Städtische Kliniken Oldenburg, Germany, F. del Valle; Caritasklinik St. Theresia Saarbrücken, Germany, J. Preiß; Bürgerhospital, Stuttgart, Germany, W. Grimminger; Katharinenhospital Stuttgart, Germany, H. G. Mergenthaler; Krankenhaus der Barmherzigen Brüder, Trier, Germany, W. Weber; and Hanusch-Krankenhaus, Wien, Austria, E. Koller.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank the members of the AML Study Group Ulm for providing leukemia specimens.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

Supported by grants P.671 and P.726 from the Medical Faculty of the University of Ulm, Germany, and by grant 01GI9981 from the Bundesministerium für Bildung und Forschung (Kompetenznetz, "Akute und chronische Leukämien"), Germany.

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Submitted June 16, 2003; accepted October 29, 2003.

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