|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2002-03-0990.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Département d'Hématologie and
INSERM U524, Hôpital Claude Huriez, Lille, France;
Département d'Hématologie and INSERM U462, Hôpital
Saint-Louis, Paris, France; and Département d'Hématologie,
Hôpital Edouard Herriot, Lyon, France.
The transcription factor C/EBP In acute myeloid leukemia (AML), genetic
abnormalities frequently occur in transcriptional control elements,
leading to uncontrolled proliferation and/or differentiation arrest.
Transcription factors belonging to the CCAAT/enhancer binding protein
(C/EBP) family have been demonstrated to be involved in the balance
between cell proliferation and mitotic growth arrest during terminal
differentiation.1,2 In the hematopoietic system, one
member of this family, C/EBP Recently, mutations of the gene coding for C/EBP In the present study, we evaluated the clinical features and the
prognostic significance associated with CEBPA mutations in 135 patients with AML, all prospectively enrolled in a common prospective randomized trial. We confirm the prevalence of these mutations in an adult AML population with a higher incidence in patients from the intermediate risk cytogenetic subgroup. We also report a clear positive impact of these CEBPA mutations on
patient outcome, leading us to propose taking into account the C/EBP Patients and samples
Treatments
CEBPA mutation detection The CEBPA mutation detection was performed by direct sequencing. According to Pabst et al,7 we used 2 overlapping primer pairs (PP1 and PP2) to amplify the entire coding region of the human CEBPA gene. Four additive primer pairs, PP3, PP4, PP5, and PP6, were used in cases of abnormal or ambiguous results. Polymerase chain reaction (PCR) was carried out in a final volume of 50 µL containing genomic DNA (100 ng), Tris (tris(hydroxymethyl)aminomethane)-HCl (40 mmol, pH 9.3), 5% dimethyl sulfoxide (DMSO), Triton X-100 (0.1%), KOAc (85 mmol), Mg(Oac)2 (1 mmol), GC melt (supplied by the manufacturer) (1 mol), 0.3 µmol of each primer, nucleotides (200 µmol of each deoxyribonucleoside triphosphate [dNTP]), and Tth DNA polymerase (0.5 units; Clontech, Palo Alto, CA). PCR conditions were as follows: 94°C for 5 minutes, 35 cycles at 94°C for 1 minute, 58°C for 1 minute, 72°C for 1 minute and 30 seconds, and then a final step for 10 minutes at 72°C. PCR products were loaded on ethidium bromide staining agarose gel, purified (Qiagen, Valencia, CA), and directly sequenced using ABIprism BigDye Terminators and AmpliTaq FS (Perkin Elmer, Foster City, CA). Abnormal sequencing results were controlled by 3 separate experiments. In cases with 2 different mutations, we amplified the coding sequence with the PP7 primer pairs corresponding to the PP1 forward primers and PP2 reverse primer, respectively. After purification, the PCR product was cloned in PCR II plasmids, and 10 clones were sequenced in each patient.Statistical analysis Response to initial therapy was evaluated after induction or after induction and salvage. Complete remission (CR) was defined according to the National Cancer Institute (NCI) criteria.12 Disease-free survival (DFS) was calculated as survival without relapse or death from the date of first CR. Event-free survival (EFS) was calculated from the date of up-front randomization until the date of CR induction failure, first relapse, or death in CR. Patient characteristics and CR rate comparisons were performed using the Fisher exact test for binary variables and the Mann-Whitney test for continuous variables. Data on treatment failure were estimated by the Kaplan-Meier method13 and compared using the log-rank test.14 Survival comparisons were adjusted for covariates using the Cox model15 and tested by the likelihood ratio test. For all outcome estimations, the 14 patients who received an allogeneic transplantation in first CR were censored at transplantation time. This was done to not introduce biases related to a putative better antileukemic effect and a higher treatment-related mortality associated with allogeneic transplantation. P < .05 was considered to indicate statistical significance. All calculations were performed using the STATA software, version 7.0 (Stata, College Station, TX).
Incidence of CEBPA mutations Direct sequencing showed 22 CEBPA mutations in 15 (11%) of 135 AML patients (Table 1). In addition, the 836T>G polymorphism was observed in 24 patients (17%), and 1 patient presented a 719C>T (H191H) silent mutation. Twelve of the 22 CEBPA mutations (Table 1, patients 1 to 12) were located in the N-terminal part of the protein (Figure 1). As indicated in Figure 2A, all these mutations induced a stop codon respectively at codon 59 (1 case), 106 (1 case), 107 (2 cases), 108 (2 cases), 159 (4 cases), 160 (1 case), and 161 (1 case). Interestingly, these 12 mutations abolished the expression of the full-length 42-kDa protein, with a normal expression of the 30-kDa protein. Eight of the 10 remaining mutations (Table 1, patients 7 to 12 and patient 15) are located in the bZip domain (Figure 1). They included duplication of Lys312 in 2 cases, addition of His at codon 307, addition of Leu at codon 304, deletion of Val-Glu307-308 with a substitution of Asn306Lys, deletion of 4 bps (1188-1191) inducing a 383 stop codon, and 2 deletions of 4 and 6 AA (Figure 2B). The 2 remaining mutations (Table 1, patients 12 and 13) were 2 large deletions of 13 and 52 bps inducing a stop codon at codon 313 and 310, respectively (Figure 2C). Overall, 7 of the 15 patients (patients 7 to 12 and patient 15) had 2 different mutations, and 1 additional patient (patient 14) had 1 in-frame deletion associated with the absence of the normal allele. The 2 alleles are implicated in all these 7 patients except one (patient 8). Finally, sequencing was performed at diagnosis and after CR achievement in 2 cases, and no mutation was detected in CR.
As indicated in Table 2, there were no
significant differences in age, sex ratio, and WBC at diagnosis between
CEBPA-mutated and CEBPA-nonmutated patients, but
CEBPA mutations were significantly associated with the M1
subtype of the French-American-British (FAB) classification
(P = .02 by the Fisher exact test). Patients with or
without CEBPA mutations were equally distributed among the 3 randomization arms.
Outcome of patients with CEBPA mutations A total of 106 (79%) of the 135 patients achieved CR. In univariate analysis, the CR rate was not significantly different in patients with or without CEBPA mutations (87% vs 78%; P = .74 by the Fisher exact test). As indicated in Figure 3, overall survival was longer in patients with CEBPA-mutated AML compared with those with CEBPA-nonmutated AML. At 5 years, estimated overall survival was 53% (95% confidence interval [CI], 25%-74%) in the former group and 25% (95% CI, 17%-34%) in the latter group (P = .04 by the log-rank test). This good prognosis associated with CEBPA mutations was also observed in terms of EFS and DFS (P = .04 and .05, respectively, by the log-rank test). In the CEBPA-nonmutated group, no difference in outcome was observed between patients presenting the 836T>G polymorphism or not (not shown).
Interaction with cytogenetics A total of 120 of the 135 patients had informative cytogenetics (Table 2). CEBPA mutations were only observed in patients from the intermediate MRC cytogenetic risk subgroup (incidence of CEBPA mutations, 16% in the intermediate subgroup vs 0% in the favorable, adverse, and undetermined subgroups; P = .06 by the Fisher exact test). In univariate analysis, this MRC classification had a strong prognostic value for CR achievement (CR rate, 15 of 15, 74 of 91, 6 of 14, and 12 of 15 in the favorable, intermediate, adverse, and undetermined subgroup, respectively; P = .002 by the Fisher exact test) as well as for outcome (P < .001 for overall survival and EFS and P = .02 for DFS by the log-rank test). Overall survival according to the 3 subgroups of the MRC cytogenetic risk classification (favorable, intermediate, and adverse) is shown on Figure 4A. However, this classification did not allow significant discrimination of patients from the favorable subgroup (with CBF-AML) from those from the intermediate subgroup (P = .32, .83, and .19 for EFS, DFS, and overall survival, respectively, by the log-rank test). This may be related to the relatively limited number of patients included in the present study and/or to the fact that survival of patients with CEBPA-mutated AML (most from the intermediate subgroup) appeared to be as good as survival of patients with CBF-AML from the favorable subgroup (Figures 3 and 4A).
Interaction with FLT3-ITD A total of 134 of the 135 patients were tested for the presence of FLT3-ITD. Overall, FLT3-ITD was detected in 35 patients studied (26%) and was also associated with the intermediate cytogenetic risk subgroup (ratio of FLT3-ITD cases, 0 of 15, 26 of 90, 3 of 14, and 6 of 15 in the favorable, intermediate, adverse, and undetermined cytogenetic risk subgroups, respectively; P = .04 by the Fisher exact test). The complete remission rate was identical in both FLT3-wt and FLT3-ITD subgroups (81% vs 77%, respectively; P = .63 by the Fisher exact test). In univariate analysis, the presence of FLT3-ITD was predictive of shortened overall survival (P = .03 by the log-rank test) but not significantly shortened EFS or DFS (P = .12 and .11, respectively, by the log-rank test). As indicated in Table 2, there was no difference in the incidence of FLT3-ITD between both CEBPA-nonmutated and CEBPA-mutated patient groups (P = .54 by the Fisher exact test). When analyzed in a 2-variable Cox model, both CEBPA mutations and FLT3-ITDs were independent factors for overall survival (P = .05 for CEBPA mutations, relative risk [RR] = 2.2 in the CEBPA-nonmutated group; P = .03 for FLT3-ITD, RR = 1.6 in the FLT3-ITD group). The 4-subgroup classification based on both C/EBP and FLT3 status
(C/EBP+/FLT3-wt,
C/EBP+/FLT3-ITD,
C/EBP /FLT3-wt,
C/EBP/FLT3-ITD) significantly
influenced overall survival (P = .03 by the log-rank
test). Furthermore, even if numbers of patients in each subgroup were
not high enough to strongly conclude, there seemed to be an interaction
between these 2 prognostic factors: presence of FLT3-ITD
significantly worsened overall survival in the CEBPA-mutated
group (estimated 5-year overall survival, 20% vs 69% in the
FLT3-ITD and the FLT3-wt groups, respectively;
P = .03 by the log-rank test) but not in the
CEBPA-nonmutated group (estimated 5-year overall survival,
14% vs 29% in the FLT3-ITD and the FLT3-wt
groups, respectively; P = .11 by the log-rank test).
Multivariate analysis We tested the prognostic significance of CEBPA mutations and FLT3-ITD in a multivariate analysis also including the 3-subgroup MRC cytogenetic risk classification as covariate. The lack of prognostic value of other putative prognostic factors including age (tested as continuous variable), WBC (tested as continuous variable), and treatment arm was verified in univariate analysis before performing this multivariate analysis (not shown). As shown in Table 3, the presence of CEBPA gene mutations represented an independent good prognosis factor in this setting, either for EFS, DFS, or overall survival (P = .04, .05, and .05, respectively). In this multivariate analysis, the presence of FLT3-ITDs was only associated with a nonsignificant trend for a worse overall survival (P = .07).
We therefore tested another risk classification in which all AML cases
with CEBPA mutation were considered as favorable if not
associated with FLT3-ITD and/or adverse cytogenetic features (Table 4). This risk classification
appeared to be more powerful than the MRC risk classification,
especially in identifying a subgroup of favorable AML that would
include all CBF-AMLs and all AMLs with CEBPA mutation but
without FLT3-ITD and/or adverse cytogenetic features.
Patients from this current favorable risk subgroup, accounting for 21%
of all cases, had significantly longer EFS and overall survival than
those from the intermediate risk subgroup (P = .01 and
.007, respectively, by the log-rank test) (Figure 4B for overall
survival). In a multivariate analysis including this current risk
classification, CEBPA mutation, and FLT3-ITD as
covariates, the risk classification remained the only independent prognostic factor for EFS, DFS, and overall survival (Table 3).
Results of this study of CEBPA gene mutations in
patients with de novo AML confirm the previously reported incidence of
these mutations in AML cells of approximately 10%. These
mutations may be categorized in 3 subclasses according to their effects
on C/EBP Results of this first prognostic study of CEBPA gene
mutations in patients with de novo AML show that CEBPA
mutations are associated with better outcome. We thus propose taking
into account the C/EBP The good outcome reported here in patients with
CEBPA-mutated AML suggests that we define a new
group of good-risk AML including PML-RAR In conclusion, while awaiting further observations emerging from the microarray technology, a simple approach based on standard karyotype associated with molecular analysis of a limited number of genes, including CBFs, FLT3, and CEBPA, provides a powerful risk classification that can be used to stratify the treatment of patients with de novo AML. This approach might still be improved through further evaluation of the prognostic significance of additional mutations of other important genes, such as p53, ras, and c-kit, in this context.
The authors are indebted to N. Philippe, M. Crepin, and the Institut Fédératif de Recherche for their excellent technical assistance and support in molecular biology and to Dr Helene Cavé and Dr Gerard Socié for helpful discussions and critical review of the manuscript.
Submitted March 29, 2002; accepted June 6, 2002.
Prepublished online as Blood First Edition Paper, June 14, 2002; DOI 10.1182/blood-2002-03-0990.
Supported by the Centre Hospitalier Universitaire of Lille (PHRC 1997), the Ligue Nationale Contre le Cancer (Comité du Nord), and the Fondation de France.
C.P. and C.S. contributed equally to the manuscript.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Claude Preudhomme, Inserm U524, Laboratoire d'Hématologie, CHRU de Lille, Hôpital Calmette Bd du Pr Leclerq, 59037 Lille, France; e-mail: cpreudhomme{at}chru-lille.fr.
1.
McKnight SL.
McBindall
2.
Lekstrom-Himes J, Xanthopoulos KG.
Biological role of the CCAAT/enhancer-binding protein family of transcription factors.
J Biol Chem.
1998;273:28545-28548
3.
Tenen DG, Hromas R, Licht JD, Zhang DE.
Transcription factors, normal myeloid development, and leukemia.
Blood.
1997;90:489-519
4.
Johansen LM, Iwama A, Lodie TA, et al.
c-Myc is a critical target for C/EBP
5.
Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG.
Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein
6.
Tenen DG.
Abnormalities of the CEBP
7.
Pabst T, Mueller BU, Zhang P, et al.
Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-
8.
Gombart AF, Hofmann WK, Kawano S, et al.
Mutations in the gene coding for the transcription factor CCAAT/enhancer binding protein
9.
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.
1998;92:2322-2333 10. Boissel N, Cayuela JM, Preudhomme C, et al. Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy. Leukemia. In press. 11. Castaigne S, Archimbaud E, Bordessoule D, et al. Sequential induction or double induction chemotherapy increase disease-free survival compared to "3+7" chemotherapy in less than 50 years adults with acute myeloid leukemia [abstract]. Blood. 1996;88(suppl 1):291a. 12. 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. 1990;8:813-819[Abstract]. 13. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481[CrossRef]. 14. Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc. 1972;135:185-206. 15. Cox D. Regression models and life-tables. J R Stat Soc. 1972;34:187-220.
16.
Williamson EA, Xu HN, Gombart AF, et al.
Identification of transcriptional activation and repression domains in human CCAAT/enhancer-binding protein epsilon.
J Biol Chem.
1998;273:14796-14804 17. Williams SC, Angerer ND, Johnson PF. C/EBP proteins contain nuclear localization signals imbedded in their basic regions. Gene Expr. 1997;6:371-385[Medline] [Order article via Infotrieve]. 18. Fröhling S, Breitruck J, Schlenk R, et al. FLT3 internal tandem duplications and survival in adult acute myeloid leukemia: analysis of 188 intensively treated patients [abstract]. Blood. 2001;98:717a.
19.
Pabst T, Mueller BU, Harakawa N, et al.
AML1-ETO downregulates the granulocytic differentiation factor C/EBP
20.
Lodie TA, Radomska HS, Donato JD, et al.
PML/RARa induces ATRA-sensitive delocalization of the critical granulocytic differentiation factor C/EBP
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  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]
|
|
|
|
|
|
C. Preudhomme, A. Renneville, V. Bourdon, N. Philippe, C. Roche-Lestienne, N. Boissel, N. Dhedin, J.-M. Andre, P. Cornillet-Lefebvre, A. Baruchel, et al. High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder Blood, May 28, 2009; 113(22): 5583 - 5587. [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]
|
|
|
|
|
|
L. Terriou, R. Ben Abdelali, C. Roumier, L. Lhermitte, J. de Vos, P. Cornillet, O. Nibourel, K. Beldjord, H. Dombret, G. Leverger, et al. C/EBPA methylation is common in T-ALL but not in M0 AML Blood, February 19, 2009; 113(8): 1864 - 1866. [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]
|
|
|
|
 |
|
 F. Lo-Coco, A. Cuneo, F. Pane, D. Cilloni, D. Diverio, M. Mancini, N. Testoni, A. Bardi, B. Izzo, N. Bolli, et al. Prognostic impact of genetic characterization in the GIMEMA LAM99P multicenter study for newly diagnosed acute myeloid leukemia Haematologica, July 1, 2008; 93(7): 1017 - 1024. [Abstract] [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]
|
|
|
|
|
|
M. Jongen-Lavrencic, S. M. Sun, M. K. Dijkstra, P. J. M. Valk, and B. Lowenberg MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia Blood, May 15, 2008; 111(10): 5078 - 5085. [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]
|
|
|
|
|
|
M. S. Hasemann, I. Damgaard, M. B. Schuster, K. Theilgaard-Monch, A. B. Sorensen, A. Mrsic, T. Krugers, B. Ylstra, F. S. Pedersen, C. Nerlov, et al. Mutation of C/EBP{alpha} predisposes to the development of myeloid leukemia in a retroviral insertional mutagenesis screen Blood, April 15, 2008; 111(8): 4309 - 4321. [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]
|
|
|
|
|
|
M. Geletu, M. Y. Balkhi, A. A. Peer Zada, M. Christopeit, J. A. Pulikkan, A. K. Trivedi, D. G. Tenen, and G. Behre Target proteins of C/EBP{alpha}p30 in AML: C/EBP{alpha}p30 enhances sumoylation of C/EBP{alpha}p42 via up-regulation of Ubc9 Blood, November 1, 2007; 110(9): 3301 - 3309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Schepers, A. T. J. Wierenga, D. van Gosliga, B. J. L. Eggen, E. Vellenga, and J. J. Schuringa Reintroduction of C/EBP{alpha} in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis Blood, August 15, 2007; 110(4): 1317 - 1325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Brown, E. McIntyre, R. Rau, S. Meshinchi, N. Lacayo, G. Dahl, T. A. Alonzo, M. Chang, R. J. Arceci, and D. Small The incidence and clinical significance of nucleophosmin mutations in childhood AML Blood, August 1, 2007; 110(3): 979 - 985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vempati, C. Reindl, S. K. Kaza, R. Kern, T. Malamoussi, M. Dugas, G. Mellert, S. Schnittger, W. Hiddemann, and K. Spiekermann Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential Blood, July 15, 2007; 110(2): 686 - 694. [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]
|
|
|
|
 |
|
 S. Meshinchi and R. J. Arceci Prognostic Factors and Risk-Based Therapy in Pediatric Acute Myeloid Leukemia Oncologist, March 1, 2007; 12(3): 341 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Kim, J. I. Eom, J.-W. Cheong, A. J. Choi, J. K. Lee, W. I. Yang, and Y. H. Min Protein Kinase CK2{alpha} as an Unfavorable Prognostic Marker and Novel Therapeutic Target in Acute Myeloid Leukemia Clin. Cancer Res., February 1, 2007; 13(3): 1019 - 1028. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
C. S. Wilson, G. S. Davidson, S. B. Martin, E. Andries, J. Potter, R. Harvey, K. Ar, Y. Xu, K. J. Kopecky, D. P. Ankerst, et al. Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction Blood, July 15, 2006; 108(2): 685 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Suh, J. Gooya, K. Renn, A. D. Friedman, P. F. Johnson, and J. R. Keller C/EBP{alpha} determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation Blood, June 1, 2006; 107(11): 4308 - 4316. [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]
|
|
|
|
 |
|
 W.-C. Chou, J.-L. Tang, L.-I. Lin, M. Yao, W. Tsay, C.-Y. Chen, S.-J. Wu, C.-F. Huang, R.-J. Chiou, M.-H. Tseng, et al. Nucleophosmin Mutations in De novo Acute Myeloid Leukemia: The Age-Dependent Incidences and the Stability during Disease Evolution. Cancer Res., March 15, 2006; 66(6): 3310 - 3316. [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]
|
|
|
|
|
|
C. D. Baldus, C. Thiede, S. Soucek, C. D. Bloomfield, E. Thiel, and G. Ehninger BAALC Expression and FLT3 Internal Tandem Duplication Mutations in Acute Myeloid Leukemia Patients With Normal Cytogenetics: Prognostic Implications J. Clin. Oncol., February 10, 2006; 24(5): 790 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Porse, T. A. Pedersen, M. S. Hasemann, M. B. Schuster, P. Kirstetter, T. Luedde, I. Damgaard, E. Kurz, C. K. Schjerling, and C. Nerlov The Proline-Histidine-Rich CDK2/CDK4 Interaction Region of C/EBP{alpha} Is Dispensable for C/EBP{alpha}-Mediated Growth Regulation In Vivo Mol. Cell. Biol., February 1, 2006; 26(3): 1028 - 1037. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. G. W. Verhaak, C. S. Goudswaard, W. van Putten, M. A. Bijl, M. A. Sanders, W. Hugens, A. G. Uitterlinden, C. A. J. Erpelinck, R. Delwel, B. Lowenberg, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance Blood, December 1, 2005; 106(12): 3747 - 3754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Boissel, A. Renneville, V. Biggio, N. Philippe, X. Thomas, J.-M. Cayuela, C. Terre, I. Tigaud, S. Castaigne, E. Raffoux, et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype Blood, November 15, 2005; 106(10): 3618 - 3620. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gery, A. F. Gombart, W. S. Yi, C. Koeffler, W.-K. Hofmann, and H. P. Koeffler Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia Blood, October 15, 2005; 106(8): 2827 - 2836. [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]
|
|
|
|
|
|
F. Rosenbauer, S. Koschmieder, U. Steidl, and D. G. Tenen Effect of transcription-factor concentrations on leukemic stem cells Blood, September 1, 2005; 106(5): 1519 - 1524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Haferlach, A. Kohlmann, S. Schnittger, M. Dugas, W. Hiddemann, W. Kern, and C. Schoch Global approach to the diagnosis of leukemia using gene expression profiling Blood, August 15, 2005; 106(4): 1189 - 1198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Helbling, B. U. Mueller, N. A. Timchenko, J. Schardt, M. Eyer, D. R. Betts, M. Jotterand, S. Meyer-Monard, M. F. Fey, and T. Pabst CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16) Blood, August 15, 2005; 106(4): 1369 - 1375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. T. Porse, D. Bryder, K. Theilgaard-Monch, M. S. Hasemann, K. Anderson, I. Damgaard, S. E. W. Jacobsen, and C. Nerlov Loss of C/EBP{alpha} cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage J. Exp. Med., July 5, 2005; 202(1): 85 - 96. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
D. Helbling, B. U. Mueller, N. A. Timchenko, A. Hagemeijer, M. Jotterand, S. Meyer-Monard, A. Lister, J. D. Rowley, B. Huegli, M. F. Fey, et al. The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin PNAS, September 7, 2004; 101(36): 13312 - 13317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Halmos, D. S. Basseres, S. Monti, F. D'Alo, T. Dayaram, K. Ferenczi, B. J. Wouters, C. S. Huettner, T. R. Golub, and D. G. Tenen A Transcriptional Profiling Study of CCAAT/Enhancer Binding Protein Targets Identifies Hepatocyte Nuclear Factor 3{beta} as a Novel Tumor Suppressor in Lung Cancer Cancer Res., June 15, 2004; 64(12): 4137 - 4147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J.M. Valk, R. G.W. Verhaak, M. A. Beijen, C. A.J. Erpelinck, S. B. v. W. van Doorn-Khosrovani, J. M. Boer, H. B. Beverloo, M. J. Moorhouse, P. J. van der Spek, B. Lowenberg, et al. Prognostically Useful Gene-Expression Profiles in Acute Myeloid Leukemia N. Engl. J. Med., April 15, 2004; 350(16): 1617 - 1628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schwieger, J. Lohler, M. Fischer, U. Herwig, D. G. Tenen, and C. Stocking A dominant-negative mutant of C/EBP{alpha}, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse Blood, April 1, 2004; 103(7): 2744 - 2752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Frohling, R. F. Schlenk, I. Stolze, J. Bihlmayr, A. Benner, S. Kreitmeier, K. Tobis, H. Dohner, and K. Dohner CEBPA Mutations in Younger Adults With Acute Myeloid Leukemia and Normal Cytogenetics: Prognostic Relevance and Analysis of Cooperating Mutations J. Clin. Oncol., February 15, 2004; 22(4): 624 - 633. [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]
|
|
|
|
|
|
S. E. Ross, H. S. Radomska, B. Wu, P. Zhang, J. N. Winnay, L. Bajnok, W. S. Wright, F. Schaufele, D. G. Tenen, and O. A. MacDougald Phosphorylation of C/EBP{alpha} Inhibits Granulopoiesis Mol. Cell. Biol., January 15, 2004; 24(2): 675 - 686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Ley, P. J. Minx, M. J. Walter, R. E. Ries, H. Sun, M. McLellan, J. F. DiPersio, D. C. Link, M. H. Tomasson, T. A. Graubert, et al. A pilot study of high-throughput, sequence-based mutational profiling of primary human acute myeloid leukemia cell genomes PNAS, November 25, 2003; 100(24): 14275 - 14280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. D'Alo', L. M. Johansen, E. A. Nelson, H. S. Radomska, E. K. Evans, P. Zhang, C. Nerlov, and D. G. Tenen The amino terminal and E2F interaction domains are critical for C/EBP{alpha}-mediated induction of granulopoietic development of hematopoietic cells Blood, November 1, 2003; 102(9): 3163 - 3171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Cilloni, S. Carturan, E. Gottardi, F. Messa, E. Messa, M. Fava, D. Diverio, A. Guerrasio, F. Lo-Coco, and G. Saglio Down-modulation of the C/EBP{alpha} transcription factor in core binding factor acute myeloid leukemias Blood, October 1, 2003; 102(7): 2705 - 2706. [Full Text] [PDF]
|
|
|
|
|
|
C. D. Baldus, S. M. Tanner, A. S. Ruppert, S. P. Whitman, K. J. Archer, G. Marcucci, M. A. Caligiuri, A. J. Carroll, J. W. Vardiman, B. L. Powell, et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study Blood, September 1, 2003; 102(5): 1613 - 1618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. U. Mueller, T. Pabst, M. Osato, N. Asou, L. M. Johansen, M. D. Minden, G. Behre, W. Hiddemann, Y. Ito, and D. G. Tenen Heterozygous PU.1 mutations are associated with acute myeloid leukemia Blood, March 1, 2003; 101(5): 2074 - 2074. [Full Text] [PDF]
|
|
|
|
|
|
B. Lowenberg, J. D. Griffin, and M. S. Tallman Acute Myeloid Leukemia and Acute Promyelocytic Leukemia Hematology, January 1, 2003; 2003(1): 82 - 101. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
7, 
-MYH11-positive AML as well as CEBPA-mutated AML. The main common
characteristic of this new group, which may account for 25% to 30% of
all de novo AML cases, might be an acquired deficiency in normal
C/EBP
a better name for CCAAT/enhancer binding proteins?
Cell.
2001;107:259-261