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

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fröhling, S. Articles by Döhner, K. Search for Related Content PubMed PubMed Citation Articles by Fröhling, S. Articles by Döhner, K. Related Articles Related Editorial Related Correspondence Social Bookmarking                            What's this?

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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
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

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
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.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
1. Bloomfield CD, Lawrence D, Byrd JC, et al: Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subgroup. Cancer Res 58:4173–4179, 1998[Abstract/Free Full Text]

2. Byrd JC, Mrózek K, Dodge RK, et al: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325–4336, 2002[Abstract/Free Full Text]

3. Grimwade D, Walker H, Oliver F, et al: The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. Blood 92:2322–2333, 1998[Abstract/Free Full Text]

4. Mrózek K, Heinonen K, Bloomfield CD: Clinical importance of cytogenetics in acute myeloid leukaemia. Baillieres Best Pract Res Clin Haematol 14:19–47, 2001

5. Slovak ML, Kopecky KJ, Cassileth PA, et al: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: A Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 96:4075–4083, 2000[Abstract/Free Full Text]

6. Döhner K, Tobis K, Ulrich R, et al: Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: A study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol 20:3254–3261, 2002[Abstract/Free Full Text]

7. Fröhling S, Schlenk RF, Breitruck J, et al: Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: A study of the AML Study Group Ulm. Blood 100:4372–4380, 2002[Abstract/Free Full Text]

8. Kottaridis PD, Gale RE, Frew ME, et al: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: Analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98:1752–1759, 2001[Abstract/Free Full Text]

9. Thiede C, Steudel C, Mohr B, et al: Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: Association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99:4326–4335, 2002[Abstract/Free Full Text]

10. van Waalwijk van Doorn-Khosrovani SB, Erpelinck C, van Putten WL, et al: High EVI1 expression predicts poor survival in acute myeloid leukemia: A study of 319 de novo AML patients. Blood 101:837–845, 2003[Abstract/Free Full Text]

11. Whitman SP, Archer KJ, Feng L, et al: Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: A Cancer and Leukemia Group B study. Cancer Res 61:7233–7239, 2001[Abstract/Free Full Text]

12. Tenen DG: Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer 3:89–101, 2003[CrossRef][Medline]

13. Tenen DG, Hromas R, Licht JD, et al: Transcription factors, normal myeloid development, and leukemia. Blood 90:489–519, 1997[Free Full Text]

14. Ward AC, Loeb DM, Soede-Bobok AA, et al: Regulation of granulopoiesis by transcription factors and cytokine signals. Leukemia 14:973–990, 2000[CrossRef][Medline]

15. Radomska HS, Huettner CS, Zhang P, et al: CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol 18:4301–4314, 1998[Abstract/Free Full Text]

16. Scott LM, Civin CI, Rorth P, et al: A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells. Blood 80:1725–1735, 1992[Abstract/Free Full Text]

17. Wang X, Scott E, Sawyers CL, et al: C/EBP by-passes G-CSF signals to rapidly induce PU.1 gene expression, stimulate granulocytic differentiation, and limit proliferation in 32D cl3 myeloblasts. Blood 94:560–571, 1999[Abstract/Free Full Text]

18. Smith LT, Hohaus S, Gonzalez DA, et al: PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Blood 88:1234–1247, 1996[Abstract/Free Full Text]

19. Hohaus S, Petrovick MS, Voso MT, et al: PU.1 (Spi-1) and C/EBP alpha regulate expression of the granulocyte-macrophage colony-stimulating factor receptor alpha gene. Mol Cell Biol 15:5830–5845, 1995[Abstract]

20. Oelgeschlager M, Nuchprayoon I, Luscher B, et al: C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase promoter. Mol Cell Biol 16:4717–4725, 1996[Abstract]

21. Ford AM, Bennett CA, Healy LE, et al: Regulation of the myeloperoxidase enhancer binding proteins Pu1, C-EBP alpha, -beta, and -delta during granulocyte-lineage specification. Proc Natl Acad Sci U S A 93:10838–10843, 1996[Abstract/Free Full Text]

22. Khanna-Gupta A, Zibello T, Simkevich C, et al: Sp1 and C/EBP are necessary to activate the lactoferrin gene promoter during myeloid differentiation. Blood 95:3734–3741, 2000[Abstract/Free Full Text]

23. Behre G, Singh SM, Liu H, et al: Ras signaling enhances the activity of C/EBP alpha to induce granulocytic differentiation by phosphorylation of serine 248. J Biol Chem 277:26293–26299, 2002[Abstract/Free Full Text]

24. Friedman AD, McKnight SL: Identification of two polypeptide segments of CCAAT/enhancer-binding protein required for transcriptional activation of the serum albumin gene. Genes Dev 4:1416–1426, 1990[Abstract/Free Full Text]

25. Lekstrom-Himes J, Xanthopoulos KG: Biological role of the CCAAT/enhancer-binding protein family of transcription factors. J Biol Chem 273:28545–28548, 1998[Abstract/Free Full Text]

26. Antonson P, Xanthopoulos KG: Molecular cloning, sequence, and expression patterns of the human gene encoding CCAAT/enhancer binding protein alpha (C/EBP alpha). Biochem Biophys Res Commun 215:106–113, 1995[CrossRef][Medline]

27. Zhang DE, Zhang P, Wang ND, et al: Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A 94:569–574, 1997[Abstract/Free Full Text]

28. Gombart AF, Hofmann WK, Kawano S, et al: Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood 99:1332–1340, 2002[Abstract/Free Full Text]

29. Pabst T, Mueller BU, Zhang P, et al: Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBP alpha), in acute myeloid leukemia. Nat Genet 27:263–270, 2001[CrossRef][Medline]

30. Pabst T, Mueller BU, Harakawa N, et al: AML1-ETO downregulates the granulocytic differentiation factor C/EBP alpha in t(8;21) myeloid leukemia. Nat Med 7:444–451, 2001[CrossRef][Medline]

31. Preudhomme C, Sagot C, Boissel N, et al: Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: A study from the Acute Leukemia French Association (ALFA). Blood 100:2717–2723, 2002[Abstract/Free Full Text]

32. van Waalwijk van Doorn-Khosravani SB, Erpelinck C, Meijer J, et al: Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Hematol J 4:31–40, 2003[CrossRef][Medline]

33. Gilliland DG, Griffin JD: The roles of FLT3 in hematopoiesis and leukemia. Blood 100:1532–1542, 2002[Abstract/Free Full Text]

34. Castilla LH, Garrett L, Adya N, et al: The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nat Genet 23:144–146, 1999[CrossRef][Medline]

35. Okuda T, Cai Z, Yang S, et al: Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood 91:3134–3143, 1998[Abstract/Free Full Text]

36. Yergeau DA, Hetherington CJ, Wang Q, et al: Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet 15:303–306, 1997[CrossRef][Medline]

37. Yuan Y, Zhou L, Miyamoto T, et al: AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci U S A 98:10398–10403, 2001[Abstract/Free Full Text]

38. Beghini A, Peterlongo P, Ripamonti CB, et al: C-kit mutations in core binding factor leukemias. Blood 95:726–727, 2000[Free Full Text]

39. Gari M, Goodeve A, Wilson G, et al: C-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. Br J Haematol 105:894–900, 1999[CrossRef][Medline]

40. Kiyoi H, Naoe T, Nakano Y, et al: Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93:3074–3080, 1999[Abstract/Free Full Text]

41. Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria of the classification of acute myeloid leukemia. Ann Intern Med 103:620–625, 1985

42. Schlenk RF, Benner A, Hartmann F, et al: Risk-adapted postremission therapy in acute myeloid leukemia: results of the German multicenter AML HD93 treatment trial. Leukemia 17:1521–1528, 2003[CrossRef][Medline]

43. Mitelman F: ISCN (1995): An International System for Human Cytogenetic Nomenclature. Basel, Switzerland, S. Karger, 1995

44. Fischer K, Scholl C, Sàlat J, et al: Design and validation of DNA probe sets for a comprehensive interphase cytogenetic analysis of acute myeloid leukemia. Blood 88:3962–3971, 1996[Abstract/Free Full Text]

45. Fröhling S, Skelin S, Liebisch C, et al: Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia. J Clin Oncol 20:2480–2485, 2002[Abstract/Free Full Text]

46. Korn EL: Censoring distributions as a measure of follow-up in survival analysis. Stat Med 5:255–260, 1986[Medline]

47. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]

48. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748, 1959

49. Holm S: A simple sequentially rejective multiple test procedure. Scand J Stat 6:65–70, 1979

50. Cox DR: Regression models and life tables (with discussion). J R Stat Soc 34:187–220, 1972

51. Ihaka R, Gentleman R: R: A language for data analysis and graphics. J Comput Graph Stat 5:299–314, 1996[CrossRef]

52. Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8:813–819, 1990[Abstract]

53. Vinson CR, Sigler PB, McKnight SL: Scissors-grip model for DNA recognition by a family of leucine zipper proteins. Science 246:911–916, 1989[Abstract/Free Full Text]

54. Calkhoven CF, Muller C, Leutz A: Translational control of C/EBP alpha and C/EBP beta isoform expression. Genes Dev 14:1920–1932, 2000[Abstract/Free Full Text]

55. Ossipow V, Descombes P, Schibler U: CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials. Proc Natl Acad Sci U S A 90:8219–8223, 1993[Abstract/Free Full Text]

56. Lodie TA, Radomska HS, Donato LD, et al: PML/RARa induces ATRA-sensitive delocalization of the critical granulocytic differentiation factor C/EBP alpha to a microspeckled nuclear pattern in t(15;17) APL. Blood 94:692a, 1999 (abstr)

57. Truong BT, Lee YJ, Lodie TA, et al: CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood 101:1141–1148, 2003[Abstract/Free Full Text]

58. Iwasaki-Arai J, Zhang P, Huettner CS, et al: C/EBP alpha deficiency in hematopoiesis induces accumulation of non-malignant myeloblasts mimicking acute myelogenous leukemia. Blood 100:61a, 2002 (abstr)

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• Loss of C/EBP and Favorable Prognosis of Acute Myeloid Leukemias: A Biological Paradox
  Danilo Perrotti, Guido Marcucci, and Michael A. Caligiuri
  JCO 2004 22: 582-584 [Full Text]

Related Correspondence

• Genetic Changes of CEBPA in Cancer: Mutations or Polymorphisms?
  Carlos Resende, Gonçalo Regalo, Cecília Durães, Fátima Carneiro, and José C. Machado
  JCO 2007 25: 2493-2494 [Full Text]

This article has been cited by other articles:

				R. Tang, P. Hirsch, F. Fava, S. Lapusan, C. Marzac, I. Teyssandier, J. Pardo, J.-P. Marie, and O. Legrand High Id1 expression is associated with poor prognosis in 237 patients with acute myeloid leukemia Blood, October 1, 2009; 114(14): 2993 - 3000. [Abstract] [Full Text] [PDF]

				T. Pabst and B. U. Mueller Complexity of CEBPA Dysregulation in Human Acute Myeloid Leukemia Clin. Cancer Res., September 1, 2009; 15(17): 5303 - 5307. [Abstract] [Full Text] [PDF]

				I. Radtke, C. G. Mullighan, M. Ishii, X. Su, J. Cheng, J. Ma, R. Ganti, Z. Cai, S. Goorha, S. B. Pounds, et al. Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia PNAS, August 4, 2009; 106(31): 12944 - 12949. [Abstract] [Full Text] [PDF]

				P. A. Ho, T. A. Alonzo, R. B. Gerbing, J. Pollard, D. L. Stirewalt, C. Hurwitz, N. A. Heerema, B. Hirsch, S. C. Raimondi, B. Lange, et al. Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group Blood, June 25, 2009; 113(26): 6558 - 6566. [Abstract] [Full Text] [PDF]

				F. Schneider, E. Hoster, M. Unterhalt, S. Schneider, A. Dufour, T. Benthaus, G. Mellert, E. Zellmeier, S. K. Bohlander, M. Feuring-Buske, et al. NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS) Blood, May 21, 2009; 113(21): 5250 - 5253. [Abstract] [Full Text] [PDF]

				A. Renneville, N. Boissel, N. Gachard, D. Naguib, C. Bastard, S. de Botton, O. Nibourel, C. Pautas, O. Reman, X. Thomas, et al. The favorable impact of CEBPA mutations in patients with acute myeloid leukemia is only observed in the absence of associated cytogenetic abnormalities and FLT3 internal duplication Blood, May 21, 2009; 113(21): 5090 - 5093. [Abstract] [Full Text] [PDF]

				B. J. Wouters, B. Lowenberg, C. A. J. Erpelinck-Verschueren, W. L. J. van Putten, P. J. M. Valk, and R. Delwel Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome Blood, March 26, 2009; 113(13): 3088 - 3091. [Abstract] [Full Text] [PDF]

				M. E. Figueroa, B. J. Wouters, L. Skrabanek, J. Glass, Y. Li, C. A. J. Erpelinck-Verschueren, A. W. Langerak, B. Lowenberg, M. Fazzari, J. M. Greally, et al. Genome-wide epigenetic analysis delineates a biologically distinct immature acute leukemia with myeloid/T-lymphoid features Blood, March 19, 2009; 113(12): 2795 - 2804. [Abstract] [Full Text] [PDF]

				O. K. Weinberg, M. Seetharam, L. Ren, K. Seo, L. Ma, J. D. Merker, J. Gotlib, J. L. Zehnder, and D. A. Arber Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system Blood, February 26, 2009; 113(9): 1906 - 1908. [Abstract] [Full Text] [PDF]

				S. Koschmieder, B. Halmos, E. Levantini, and D. G. Tenen Dysregulation of the C/EBP{alpha} Differentiation Pathway in Human Cancer J. Clin. Oncol., February 1, 2009; 27(4): 619 - 628. [Abstract] [Full Text] [PDF]

				R. F. Schlenk, K. Dohner, M. Kneba, K. Gotze, F. Hartmann, F. del Valle, H. Kirchen, E. Koller, J. T. Fischer, L. Bullinger, et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B Haematologica, January 1, 2009; 94(1): 54 - 60. [Abstract] [Full Text] [PDF]

				T. Pabst, M. Eyholzer, S. Haefliger, J. Schardt, and B. U. Mueller Somatic CEBPA Mutations Are a Frequent Second Event in Families With Germline CEBPA Mutations and Familial Acute Myeloid Leukemia J. Clin. Oncol., November 1, 2008; 26(31): 5088 - 5093. [Abstract] [Full Text] [PDF]

				G. Marcucci, K. Maharry, M. D. Radmacher, K. Mrozek, T. Vukosavljevic, P. Paschka, S. P. Whitman, C. Langer, C. D. Baldus, C.-G. Liu, et al. Prognostic Significance of, and Gene and MicroRNA Expression Signatures Associated With, CEBPA Mutations in Cytogenetically Normal Acute Myeloid Leukemia With High-Risk Molecular Features: A Cancer and Leukemia Group B Study J. Clin. Oncol., November 1, 2008; 26(31): 5078 - 5087. [Abstract] [Full Text] [PDF]

				P. Paschka, G. Marcucci, A. S. Ruppert, S. P. Whitman, K. Mrozek, K. Maharry, C. Langer, C. D. Baldus, W. Zhao, B. L. Powell, et al. Wilms' Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., October 1, 2008; 26(28): 4595 - 4602. [Abstract] [Full Text] [PDF]

				J. P. Radich Molecular Classification of Acute Myeloid Leukemia: Are We There Yet? J. Clin. Oncol., October 1, 2008; 26(28): 4539 - 4541. [Full Text] [PDF]

				C. Langer, M. D. Radmacher, A. S. Ruppert, S. P. Whitman, P. Paschka, K. Mrozek, C. D. Baldus, T. Vukosavljevic, C.-G. Liu, M. E. Ross, et al. 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, June 1, 2008; 111(11): 5371 - 5379. [Abstract] [Full Text] [PDF]

				S. Meshinchi, D. L. Stirewalt, T. A. Alonzo, T. J. Boggon, R. B. Gerbing, J. L. Rocnik, B. J. Lange, D. G. Gilliland, and J. P. Radich Structural and numerical variation of FLT3/ITD in pediatric AML Blood, May 15, 2008; 111(10): 4930 - 4933. [Abstract] [Full Text] [PDF]

				R. F. Schlenk, K. Dohner, J. Krauter, S. Frohling, A. Corbacioglu, L. Bullinger, M. Habdank, D. Spath, M. Morgan, A. Benner, et al. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia N. Engl. J. Med., May 1, 2008; 358(18): 1909 - 1918. [Abstract] [Full Text] [PDF]

				L. Bullinger, K. Dohner, R. Kranz, C. Stirner, S. Frohling, C. Scholl, Y. H. Kim, R. F. Schlenk, R. Tibshirani, H. Dohner, et al. An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML Blood, May 1, 2008; 111(9): 4490 - 4495. [Abstract] [Full Text] [PDF]

				R. Garzon, M. Garofalo, M. P. Martelli, R. Briesewitz, L. Wang, C. Fernandez-Cymering, S. Volinia, C.-G. Liu, S. Schnittger, T. Haferlach, et al. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin PNAS, March 11, 2008; 105(10): 3945 - 3950. [Abstract] [Full Text] [PDF]

				U. Bacher, C. Haferlach, W. Kern, T. Haferlach, and S. Schnittger Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients Blood, March 1, 2008; 111(5): 2527 - 2537. [Abstract] [Full Text] [PDF]

				B. Lowenberg Acute Myeloid Leukemia: The Challenge of Capturing Disease Variety Hematology, January 1, 2008; 2008(1): 1 - 11. [Abstract] [Full Text] [PDF]

				T. Haferlach Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia Hematology, January 1, 2008; 2008(1): 400 - 411. [Abstract] [Full Text] [PDF]

				G. Marcucci, K. Maharry, S. P. Whitman, T. Vukosavljevic, P. Paschka, C. Langer, K. Mrozek, C. D. Baldus, A. J. Carroll, B. L. Powell, et al. 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., August 1, 2007; 25(22): 3337 - 3343. [Abstract] [Full Text] [PDF]

				C. Resende, G. Regalo, C. Duraes, F. Carneiro, and J. C. Machado Genetic Changes of CEBPA in Cancer: Mutations or Polymorphisms? J. Clin. Oncol., June 10, 2007; 25(17): 2493 - 2494. [Full Text] [PDF]

				S. Frohling, A. Corbacioglu, R. F. Schlenk, H. Dohner, and K. Dohner In Reply J. Clin. Oncol., June 10, 2007; 25(17): 2494 - 2495. [Full Text] [PDF]

				K. L. Bennett, B. Hackanson, L. T. Smith, C. D. Morrison, J. C. Lang, D. E. Schuller, F. Weber, C. Eng, and C. Plass Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein {alpha} Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma Cancer Res., May 15, 2007; 67(10): 4657 - 4664. [Abstract] [Full Text] [PDF]

				T. Akasaka, T. Balasas, L. J. Russell, K.-j. Sugimoto, A. Majid, R. Walewska, E. L. Karran, D. G. Brown, K. Cain, L. Harder, et al. Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) Blood, April 15, 2007; 109(8): 3451 - 3461. [Abstract] [Full Text] [PDF]

				B. Falini, I. Nicoletti, M. F. Martelli, and C. Mecucci Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features Blood, February 1, 2007; 109(3): 874 - 885. [Abstract] [Full Text] [PDF]

				K. Mrozek, G. Marcucci, P. Paschka, S. P. Whitman, and C. D. Bloomfield 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, January 15, 2007; 109(2): 431 - 448. [Abstract] [Full Text] [PDF]

				J. Pedersen-Bjergaard, M. T. Andersen, and M. K. Andersen Genetic Pathways in the Pathogenesis of Therapy-Related Myelodysplasia and Acute Myeloid Leukemia Hematology, January 1, 2007; 2007(1): 392 - 397. [Abstract] [Full Text] [PDF]

				B. J. Wouters, I. Louwers, P. J. M. Valk, B. Lowenberg, and R. Delwel A recurrent in-frame insertion in a CEBPA transactivation domain is a polymorphism rather than a mutation that does not affect gene expression profiling-based clustering of AML Blood, January 1, 2007; 109(1): 389 - 390. [Full Text] [PDF]

				C. Marzac, I. Teyssandier, O. Calendini, J.-Y. Perrot, A.-M. Faussat, R. Tang, N. Casadevall, J.-P. Marie, and O. Legrand Flt3 Internal Tandem Duplication and P-Glycoprotein Functionality in 171 Patients with Acute Myeloid Leukemia Clin. Cancer Res., December 1, 2006; 12(23): 7018 - 7024. [Abstract] [Full Text] [PDF]

				M. Heuser, G. Beutel, J. Krauter, K. Dohner, N. von Neuhoff, B. Schlegelberger, and A. Ganser High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics Blood, December 1, 2006; 108(12): 3898 - 3905. [Abstract] [Full Text] [PDF]

				M. D. Radmacher, G. Marcucci, A. S. Ruppert, K. Mrozek, S. P. Whitman, J. W. Vardiman, P. Paschka, T. Vukosavljevic, C. D. Baldus, J. E. Kolitz, et al. Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study Blood, September 1, 2006; 108(5): 1677 - 1683. [Abstract] [Full Text] [PDF]

				S. S. Farag, K. J. Archer, K. Mrozek, A. S. Ruppert, A. J. Carroll, J. W. Vardiman, M. J. Pettenati, M. R. Baer, M. B. Qumsiyeh, P. R. Koduru, et al. Pretreatment cytogenetics add 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, July 1, 2006; 108(1): 63 - 73. [Abstract] [Full Text] [PDF]

				U. Bacher, T. Haferlach, C. Schoch, W. Kern, and S. Schnittger Implications of NRAS mutations in AML: a study of 2502 patients Blood, May 15, 2006; 107(10): 3847 - 3853. [Abstract] [Full Text] [PDF]

				C. Thiede, S. Koch, E. Creutzig, C. Steudel, T. Illmer, M. Schaich, G. Ehninger, and for the Deutsche Studieninitiative Leukamie (DSIL) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML) Blood, May 15, 2006; 107(10): 4011 - 4020. [Abstract] [Full Text] [PDF]

				S. Chattopadhyay, E.-Y. Gong, M. Hwang, E. Park, H. J. Lee, C. Y. Hong, H.-S. Choi, J.-H. Cheong, H. B. Kwon, and K. Lee The CCAAT Enhancer-Binding Protein-{alpha} Negatively Regulates the Transactivation of Androgen Receptor in Prostate Cancer Cells Mol. Endocrinol., May 1, 2006; 20(5): 984 - 995. [Abstract] [Full Text] [PDF]

				H. S. Radomska, D. S. Basseres, R. Zheng, P. Zhang, T. Dayaram, Y. Yamamoto, D. W. Sternberg, N. Lokker, N. A. Giese, S. K. Bohlander, et al. Block of C/EBP{alpha} function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations J. Exp. Med., February 21, 2006; 203(2): 371 - 381. [Abstract] [Full Text] [PDF]

				K. Mrozek and C. D. Bloomfield Chromosome Aberrations, Gene Mutations and Expression Changes, and Prognosis in Adult Acute Myeloid Leukemia Hematology, January 1, 2006; 2006(1): 169 - 177. [Abstract] [Full Text] [PDF]

				G. Marcucci, C. D. Baldus, A. S. Ruppert, M. D. Radmacher, K. Mrozek, S. P. Whitman, J. E. Kolitz, C. G. Edwards, J. W. Vardiman, B. L. Powell, et al. 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., December 20, 2005; 23(36): 9234 - 9242. [Abstract] [Full Text] [PDF]

				S. Schnittger, C. Schoch, W. Kern, C. Mecucci, C. Tschulik, M. F. Martelli, T. Haferlach, W. Hiddemann, and B. Falini Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype Blood, December 1, 2005; 106(12): 3733 - 3739. [Abstract] [Full Text] [PDF]

				K. Dohner, R. F. Schlenk, M. Habdank, C. Scholl, F. G. Rucker, A. Corbacioglu, L. Bullinger, S. Frohling, H. Dohner, and for the AML Study Group (AMLSG) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations Blood, December 1, 2005; 106(12): 3740 - 3746. [Abstract] [Full Text] [PDF]

				K. Stegmaier, S. M. Corsello, K. N. Ross, J. S. Wong, D. J. DeAngelo, and T. R. Golub Gefitinib induces myeloid differentiation of acute myeloid leukemia Blood, October 15, 2005; 106(8): 2841 - 2848. [Abstract] [Full Text] [PDF]

				I. Paz-Priel, D. H. Cai, D. Wang, J. Kowalski, A. Blackford, H. Liu, C. A. Heckman, A. F. Gombart, H. P. Koeffler, L. M. Boxer, et al. CCAAT/Enhancer Binding Protein {alpha} (C/EBP{alpha}) and C/EBP{alpha} Myeloid Oncoproteins Induce Bcl-2 via Interaction of Their Basic Regions with Nuclear Factor-{kappa}B p50 Mol. Cancer Res., October 1, 2005; 3(10): 585 - 596. [Abstract] [Full Text] [PDF]

				S. Frohling, C. Scholl, D. G. Gilliland, and R. L. Levine Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications J. Clin. Oncol., September 10, 2005; 23(26): 6285 - 6295. [Abstract] [Full Text] [PDF]

				L. Bullinger and P. J.M. Valk Gene Expression Profiling in Acute Myeloid Leukemia J. Clin. Oncol., September 10, 2005; 23(26): 6296 - 6305. [Abstract] [Full Text] [PDF]

				M. S. Tallman, D. G. Gilliland, and J. M. Rowe Drug therapy for acute myeloid leukemia Blood, August 15, 2005; 106(4): 1154 - 1163. [Abstract] [Full Text] [PDF]

				L.-Y. Shih, C.-F. Huang, T.-L. Lin, J.-H. Wu, P.-N. Wang, P. Dunn, M.-C. Kuo, and T.-C. Tang Heterogeneous Patterns of CEBP{alpha} Mutation Status in the Progression of Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia to Acute Myelogenous Leukemia Clin. Cancer Res., March 1, 2005; 11(5): 1821 - 1826. [Abstract] [Full Text] [PDF]

				L.-I. Lin, C.-Y. Chen, D.-T. Lin, W. Tsay, J.-L. Tang, Y.-C. Yeh, H.-L. Shen, F.-H. Su, M. Yao, S.-Y. Huang, et al. Characterization of CEBPA Mutations in Acute Myeloid Leukemia: Most Patients with CEBPA Mutations Have Biallelic Mutations and Show a Distinct Immunophenotype of the Leukemic Cells Clin. Cancer Res., February 15, 2005; 11(4): 1372 - 1379. [Abstract] [Full Text] [PDF]

				S. S. Farag, A. S. Ruppert, K. Mrozek, R. J. Mayer, R. M. Stone, A. J. Carroll, B. L. Powell, J. O. Moore, M. J. Pettenati, P. R.K. Koduru, et al. Outcome of Induction and Postremission Therapy in Younger Adults With Acute Myeloid Leukemia With Normal Karyotype: A Cancer and Leukemia Group B Study J. Clin. Oncol., January 20, 2005; 23(3): 482 - 493. [Abstract] [Full Text] [PDF]

				M. S. Tallman New Strategies for the Treatment of Acute Myeloid Leukemia Including Antibodies and Other Novel Agents Hematology, January 1, 2005; 2005(1): 143 - 150. [Abstract] [Full Text] [PDF]

				S. Frohling and H. Dohner Disruption of C/EBP{alpha} Function in Acute Myeloid Leukemia N. Engl. J. Med., December 2, 2004; 351(23): 2370 - 2372. [Full Text] [PDF]

				M. L. Smith, J. D. Cavenagh, T. A. Lister, and J. Fitzgibbon Mutation of CEBPA in Familial Acute Myeloid Leukemia N. Engl. J. Med., December 2, 2004; 351(23): 2403 - 2407. [Abstract] [Full Text] [PDF]

				M. E. Ross, R. Mahfouz, M. Onciu, H.-C. Liu, X. Zhou, G. Song, S. A. Shurtleff, S. Pounds, C. Cheng, J. Ma, et al. Gene expression profiling of pediatric acute myelogenous leukemia Blood, December 1, 2004; 104(12): 3679 - 3687. [Abstract] [Full Text] [PDF]

				D. Perrotti, G. Marcucci, and M. A. Caligiuri Loss of C/EBP{alpha} and Favorable Prognosis of Acute Myeloid Leukemias: A Biological Paradox J. Clin. Oncol., February 15, 2004; 22(4): 582 - 584. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fröhling, S. Articles by Döhner, K. Search for Related Content PubMed PubMed Citation Articles by Fröhling, S. Articles by Döhner, K. Related Articles Related Editorial Related Correspondence Social Bookmarking                            What's this?