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NEOPLASIA
From Cedars-Sinai Medical Center, Burns and Allen
Research Institute, Division of Hematology/Oncology, University of
California-Los Angeles School of Medicine; Division of Hematology and
Clinical Laboratories, Keio University School of Medicine, Tokyo,
Japan; and Department of Hematology, University Hospital, Frankfurt am
Main, Germany.
The CCAAT/enhancer binding protein The CCAAT/enhancer binding protein C/EBP Targeted inactivation of C/EBP The importance of C/EBP Samples
Polymerase chain reaction-single-strand conformation polymorphism
analysis
Expression vectors
Cell lines, transfections, and analysis of protein expression NIH3T3 cells were maintained in Dulbecco modified Eagle medium supplemented with 10% bovine serum. For cellular localization, cells were plated at 70% confluency on a glass coverslip in a 35-mm dish. The cells were transfected with 3 µg MIG, MIG-C/EBP mutant, or
pCMV-C/EBP wildtype plus pEGFPc with the use of 15 µL GenePORTER,
as described by the manufacturer (Gene Therapy Systems, San Diego, CA).
At 24 hours after transfection, cells were fixed in 10% formalin for 1 hour, washed twice in phosphate-bufferend saline (PBS), and
permeablized in PBS with 0.1% Triton X-100 for 5 minutes. The cells
were incubated with rabbit anti-C/EBP antibody (SC-61) diluted to
0.01 µg/mL (Santa Cruz Biotechnology, CA) for 1 hour, washed twice
with PBS, and incubated with a 1:200 dilution of tetrarhodamine
isothiocyanate-conjugated goat antirabbit immunoglobulin G (Sigma, St
Louis). The coverslips were mounted with Gel/Mount (Biomeda, Foster
City, CA) and examined by fluorescent microscopy. Total cell protein
was prepared from NIH3T3 cells transfected with pCMV,
pCMV-C/EBP 42 wildtype (WT) or mutant expression vectors and lysed in 0.5% NP-40 buffer (50 mM Tris-HCl [pH 7.5], 150 mM NaCl, 0.5% NP-40). Western blot analysis was performed as described previously.40 The blots were incubated overnight with 0.2 µg/mL of either rabbit anti-C/EBP antiserum (Santa Cruz
Biotechology) diluted in PBS containing 5% powdered
milk.41 The primary antibodies were detected with either
donkey antirabbit-horseradish peroxidase (HRP) or antigoat-HRP
(1:5000). The complexes were developed with SuperSignal West Pico
Chemiluminescent Substrate (Pierce, Rockford, IL), as described by the
manufacturer, and detected by autoradiography.
Transcriptional activation assays For transcriptional activation assays, NIH3T3 cells were plated in a 12-well dish at 50% to 70% confluency. For each triplicate, the plasmids were prepared as a master mix of pG-CSF receptor-luciferase, pRLSV40, a renilla luciferase expression vector (Promega, Madison, WI), C/EBP expression vector, and empty vector, for a final total of 3 µg DNA. The combinations and amounts of expression vectors are
indicated in the figure legends. The plasmids in 0.5 mL Opti-MEM (Gibco/BRL) were mixed with 15 µL GenePorter in 0.5 mL Opti-MEM and
incubated 45 minutes; then, 0.33 mL were aliquoted to each well of the
12-well plate (1 µg DNA per well). The reporter plasmid pG-CSF
receptor-luciferase was generously provided by Dan
Tenen.16 At 24 hours after transfection, cells were
harvested in passive lysis buffer, and luciferase activity was measured
by means of a dual luciferase assay (Promega).
Electrophoretic mobility shift assays A double-stranded oligonucleotide containing the C/EBP site (bp 57 to 38; 5'-aaggtgttgcaatccccagc-3') of the human G-CSF receptor
promoter was end-labeled with 32P adenosine triphosphate
by means of T4 polynucleotide kinase as described by the manufacturer
(Gibco/BRL).16 The labeled oligonucleotide (1 ng per
reaction) was mixed with equal volumes of total cell extract from
NIH3T3 cells transfected with expression vectors for the different
C/EBP proteins and buffer B (20% glycerol, 20 mM Hepes [pH 7.9],
50 mM NaCl, 2 mM MgCl2, and 1 mM dithiothreitol). Poly (dI-dC)
(Amersham Pharmacia Biotech, Piscataway, NJ) and bovine serum albumin
(Sigma) were added to 50 µg/mL and 300 µg/mL final concentrations,
respectively. Reactions were incubated at room temperature for 30 minutes and analyzed by gel electrophoresis through a 4%
polyacrylamide gel with the use of a Tris-glycine buffer (50 mM Tris,
400 mM glycine, 1 mM EDTA, with pH adjusted to 8.5). For supershifts,
0.2 µg antibody was added to the reaction 30 minutes prior to
addition of the probe. Gels were exposed to Kodak XO-Mat film
(Rochester, NY).
Identification of C/EBP Absence of C/EBP
Of 227 hematologic cancers, a total of 10 mutations were identified
among 1 acute myelogenous leukemia (MDS) and 7 acute myelogenous leukemia (AML) patient samples (Table 3). The MDS sample, a refractory anemia with excess of blasts in transformation (RAEB-t), possessed biallelic mutations. Abnormally migrating bands for regions 2 and 4 (Figure 2A, lane 3) were observed.
Sequence analysis revealed that one allele acquired a 37-bp duplication
(nt 483 to 419) in region 2 that was predicted to result in a
frameshift and truncation of the protein (Figure
3). The other allele acquired a nonsense mutation (1015G>T) that would introduce a stop codon in region 4. Both
of these mutations are predicted to encode C/EBP
The AML patient samples F3901 (M4), J6 (M2), and J3 (M2) acquired a 3-bp deletion, 3-bp duplication, and 15-bp duplication, respectively, in region 4 (Figure 2C, lanes 1, 11, 14; Figure 3; Table 3). These would generate either an inframe deletion (in sample F3901) or a duplication of 1 (J6) or 5 (J3) amino acids in the first leucine zipper (Figure 4). The AML sample J2 possessed a 1001C>A nonsense mutation that would replace the Tyr284 with a termination codon (Figure 2C, lane 10; Table 3). The AML-M2 sample K-6 showed an abnormally migrating band in region 4 by SSCP (data not shown), and sequence analysis revealed a 1063G>C transversion. This missense mutation created an amino acid residue change of Arg305Pro in the fork region between the basic and the leucine zipper regions (Table 3; Figure 4). The AML-M4 sample F4431 possessed the same silent mutation 551G>A in region 2 as described for the prostate cancer (Table 3). Each of the AML-M2 samples lacked the t(8;21) translocation that produces an AML-ETO fusion (Table 3). From the PCR-SSCP analysis, it is difficult to conclude whether these samples possess a wildtype allele because potential contamination by normal cells with the subsequent amplification of the wildtype allele by PCR may occur. However, sample J6 lacks a wildtype pattern upon shorter exposure of the autoradiograph, suggesting it possesses only the mutant allele (Figure 2C, lane 14, and data not shown). Also, in a cell line derived from sample K-6, a wildtype and mutant allele were identified, indicating that the mutation is heterozygous (H. Asou et al, submitted September 2001). In addition to patient samples, 5 AML cell lines were examined
for C/EBP Wildtype and mutant C/EBP
protein, we cloned expressible complementary DNAs for the 3-bp deletion
and the 15- and 24-bp duplications into the retrovirus vector MIG that
allows coexpression of green fluorescent protein (GFP) with
the gene of interest. Each vector was transiently transfected into
NIH3T3 cells, and the nuclear localization was determined by
immunofluorescent microscopy (Figure 5).
Both the wildtype and mutant proteins localized in the nucleus. These
results indicate that the mutations do not impair the protein
localization of C/EBP to its normal cellular compartment.
Deficient transcriptional activation by mutant C/EBP
protein activated the transcription 15-fold over the empty expression
vector alone (Figure 6B). Each of the mutant proteins activated the
reporter only 2-fold over the empty expression vector, indicating a
greater than 80% reduction in transactivation function (Figure
6B).
Deficiency in DNA binding of mutant C/EBP
showed significantly higher binding activity than the mutants (Figure
6C, lanes 1, 3, 5, 7, 9). The bound DNA/protein complexes were
supershifted with rabbit anti-C/EBP antibody, verifying that the
binding activity belonged to C/EBP (Figure 6C, lanes 2, 4, 6, 8, 10). The mutants revealed a greater than 90% reduction in binding
compared with the wildtype C/EBP . These results indicate the
mutations abrogated the DNA-binding function of C/EBP .
Mutant forms of C/EBP , the wildtype protein
was coexpressed with increasing amounts of each mutant (Figure
7). The mutants were unable to activate
transcription or interfere with the ability of the wildtype C/EBP to
activate transcription. These results suggest that the mutant C/EBP
proteins lost their transactivation potential and were unable to impair wildtype C/EBP transcriptional activation of the G-CSF receptor promoter. As a positive control, the same transfections were performed with the 30-kd form of C/EBP . This shortened isoform of C/EBP attenuates transcriptional activation by
C/EBP 42.42 It is potentially expressed in
cells from patient F3820 from the other mutant allele (C381 deletion,
Table 3). As expected, a dose-dependent reduction in
C/EBP 42 transactivation was observed (Figure
7).
The growth-inhibitory and differentiation-promoting functions of
C/EBP The mutations in this report fall into 4 classes in regard to their
effect on the predicted protein: (1) termination of translation by
introducing a nonsense codon (samples J2 and F3881); (2) alteration of
amino acid sequence by introducing a missense codon (K-6); (3)
frameshift by either deletion or duplication of nucleotides and an
eventual termination (F3820 and F3881); and (4) inframe deletion or
duplication that removes or inserts additional amino acid residues
(F3901, F3820, J3, and J6). The nonsense mutations in samples J2 (AML)
and F3881 (MDS) would introduce termination codons before the bZIP
domain. This would create polypeptides that are unable to localize to
the nucleus, dimerize, and bind to DNA (Table 3).5,44 The
mutation of Arg305Pro in patient K-6 occurs in the fork region of bZIP
domain (Figure 4; Table 3). The inframe deletion and insertion
mutations of patients F3901, F3820, J3, and J6 occur within the first
conserved leucine finger (Figure 4; Table 3). Previous
structure/function studies indicate that these mutations would abrogate
C/EBP Comparison of the predicted amino acid sequences of 11 bZIP
family members reveals conservation between the basic and leucine zipper regions and the exact spatial register or phasing between these
regions, referred to as the fork (Figure 4).1 The phasing is important for a continued We hypothesized that these mutant forms would function in a
dominant-negative fashion since they may heterodimerize with the wildtype as suggested by prior studies with similar
mutations.45,46 These mutants did not attenuate
transcriptional activation by wildtype C/EBP The absence of helical-destabilizing residues, such as proline and
glycine, in the bZIP domain in all family members is consistent with
the hypothesis that phasing is critical for the bZIP
domain.1 The Arg305Pro mutation found in K-6 is predicted
to introduce a break in the Further studies are needed to determine how the different mutations
contribute to the development of leukemia. For 2 patients, F3881 and
F3820, the mutations were biallelic, and patient J6 appears to possess
only the mutant allele, suggesting that loss of C/EBP The absence of mutations in the nonhematologic malignancies was
surprising. In tissues such as liver and adipose, the lack of mutations
could be due to the small size of our collections of
hepatomas6 and liposarcomas.2 Further
screening of these tumors may be of interest. In the case of our fairly
extensive collection, one reason for the lack of mutations may be that
other mechanisms are blocking C/EBP In summary, we identified mutations of C/EBP
We are grateful to Jonathan Said for generously providing soft-tissue sarcoma samples for analysis. We thank Alexey Chumakov for helpful discussions and advice.
Submitted December 1, 2000; accepted October 4, 2001.
Supported by National Institutes of Health grant CA26038-20, Joesph Troy Leukemia Fund, Horn Foundation, Lymphoma Research Foundation of America, and C. & H. Koeffler Fund. A.F.G. is a recipient of a Lymphoma Research Foundation of America Fellowship. W.K.H. is a recipient of a fellowship (HO2207/1-1) from the Deutsche Forschungsgemeinschaft. H.P.K. holds the Mark Goodson endowed chair for Cancer Research and is a member of the Jonsson Cancer Center.
A.F.G., W.-K. H., and S. K. contributed equally to this work.
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: Adrian F. Gombart, Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Davis Bldg 5065, 8700 Beverly Blvd, Los Angeles, CA 90048; e-mail: gombarta{at}csmc.edu.
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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] |
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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] |
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T. Akagi, T. Saitoh, J. O'Kelly, S. Akira, A. F. Gombart, and H. P. Koeffler Impaired response to GM-CSF and G-CSF, and enhanced apoptosis in C/EBP{beta}-deficient hematopoietic cells Blood, March 15, 2008; 111(6): 2999 - 3004. [Abstract] [Full Text] [PDF] |
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R. Dahl C/EBP{alpha}p30 SUMO wrestles C/EBP{alpha}p42 Blood, November 1, 2007; 110(9): 3089 - 3089. [Full Text] [PDF] |
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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] |
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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] |
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J. S. Chang, R. Santhanam, R. Trotta, P. Neviani, A. M. Eiring, E. Briercheck, M. Ronchetti, D. C. Roy, B. Calabretta, M. A. Caligiuri, et al. High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBP{alpha}-driven myeloid differentiation Blood, August 1, 2007; 110(3): 994 - 1003. [Abstract] [Full Text] [PDF] |
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K. D. Loomis, S. Zhu, K. Yoon, P. F. Johnson, and R. C. Smart Genetic Ablation of CCAAT/Enhancer Binding Protein {alpha} in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis Cancer Res., July 15, 2007; 67(14): 6768 - 6776. [Abstract] [Full Text] [PDF] |
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A. F. Gombart, J. Grewal, and H. P. Koeffler ATF4 differentially regulates transcriptional activation of myeloid-specific genes by C/EBP{epsilon} and C/EBP{alpha} J. Leukoc. Biol., June 1, 2007; 81(6): 1535 - 1547. [Abstract] [Full Text] [PDF] |
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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] |
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G. Ferrari-Amorotti, K. Keeshan, M. Zattoni, C. Guerzoni, G. Iotti, S. Cattelani, N. J. Donato, and B. Calabretta Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBP{alpha} Blood, August 15, 2006; 108(4): 1353 - 1362. [Abstract] [Full Text] [PDF] |
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A. T. J. Wierenga, H. Schepers, M. A. S. Moore, E. Vellenga, and J. J. Schuringa STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBP{alpha} Blood, June 1, 2006; 107(11): 4326 - 4333. [Abstract] [Full Text] [PDF] |
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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] |
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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] |
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Y. Tada, R. M. Brena, B. Hackanson, C. Morrison, G. A. Otterson, and C. Plass Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein alpha activity in lung cancer. J Natl Cancer Inst, March 15, 2006; 98(6): 396 - 406. [Abstract] [Full Text] [PDF] |
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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] |
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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] |
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D. S. Basseres, E. Levantini, H. Ji, S. Monti, S. Elf, T. Dayaram, M. Fenyus, O. Kocher, T. Golub, K.-k. Wong, et al. Respiratory Failure Due to Differentiation Arrest and Expansion of Alveolar Cells following Lung-Specific Loss of the Transcription Factor C/EBP{alpha} in Mice Mol. Cell. Biol., February 1, 2006; 26(3): 1109 - 1123. [Abstract] [Full Text] [PDF] |
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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] |
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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] |
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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] |
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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] |
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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] |
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A. F. Gombart, N. Borregaard, and H. P. Koeffler Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3 FASEB J, July 1, 2005; 19(9): 1067 - 1077. [Abstract] [Full Text] [PDF] |
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C. Choudhary, J. Schwable, C. Brandts, L. Tickenbrock, B. Sargin, T. Kindler, T. Fischer, W. E. Berdel, C. Muller-Tidow, and H. Serve AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations Blood, July 1, 2005; 106(1): 265 - 273. [Abstract] [Full Text] [PDF] |
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T. Ikezoe, S. Gery, D. Yin, J. O'Kelly, L. Binderup, N. Lemp, H. Taguchi, and H. P. Koeffler CCAAT/Enhancer-Binding Protein {delta}: A Molecular Target of 1,25-Dihydroxyvitamin D3 in Androgen-Responsive Prostate Cancer LNCaP Cells Cancer Res., June 1, 2005; 65(11): 4762 - 4768. [Abstract] [Full Text] [PDF] |
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N. Takai, N. Kawamata, C. S. Walsh, S. Gery, J. C. Desmond, S. Whittaker, J. W. Said, L. M. Popoviciu, P. A. Jones, I. Miyakawa, et al. Discovery of Epigenetically Masked Tumor Suppressor Genes in Endometrial Cancer Mol. Cancer Res., May 1, 2005; 3(5): 261 - 269. [Abstract] [Full Text] [PDF] |
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S. Gery, S. Tanosaki, S. Bose, N. Bose, J. Vadgama, and H. P. Koeffler Down-Regulation and Growth Inhibitory Role of C/EBP{alpha} in Breast Cancer Clin. Cancer Res., May 1, 2005; 11(9): 3184 - 3190. [Abstract] [Full Text] [PDF] |
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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] |
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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] |
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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] |
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V. Heath, H. C. Suh, M. Holman, K. Renn, J. M. Gooya, S. Parkin, K. D. Klarmann, M. Ortiz, P. Johnson, and J. Keller C/EBP{alpha} deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo Blood, September 15, 2004; 104(6): 1639 - 1647. [Abstract] [Full Text] [PDF] |
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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] |
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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] |
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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] |
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C. Muller, C. F. Calkhoven, X. Sha, and A. Leutz The CCAAT Enhancer-binding Protein {alpha} (C/EBP{alpha}) Requires a SWI/SNF Complex for Proliferation Arrest J. Biol. Chem., February 20, 2004; 279(8): 7353 - 7358. [Abstract] [Full Text] [PDF] |
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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] |
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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] |
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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] |
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S. Tavor, D. J. Park, S. Gery, P. T. Vuong, A. F. Gombart, and H. P. Koeffler Restoration of C/EBP{alpha} Expression in a BCR-ABL+ Cell Line Induces Terminal Granulocytic Differentiation J. Biol. Chem., December 26, 2003; 278(52): 52651 - 52659. [Abstract] [Full Text] [PDF] |
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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] |
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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] |
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T. Kummalue and A. D. Friedman Cross-talk between regulators of myeloid development: C/EBP{alpha} binds and activates the promoter of the PU.1 gene J. Leukoc. Biol., September 1, 2003; 74(3): 464 - 470. [Abstract] [Full Text] [PDF] |
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K. Keeshan, G. Santilli, F. Corradini, D. Perrotti, and B. Calabretta Transcription activation function of C/EBP{alpha} is required for induction of granulocytic differentiation Blood, August 15, 2003; 102(4): 1267 - 1275. [Abstract] [Full Text] [PDF] |
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M. Mizuki, J. Schwable, C. Steur, C. Choudhary, S. Agrawal, B. Sargin, B. Steffen, I. Matsumura, Y. Kanakura, F. D. Bohmer, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations Blood, April 15, 2003; 101(8): 3164 - 3173. [Abstract] [Full Text] [PDF] |
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A. F. Gombart, S. H. Kwok, K. L. Anderson, Y. Yamaguchi, B. E. Torbett, and H. P. Koeffler Regulation of neutrophil and eosinophil secondary granule gene expression by transcription factors C/EBPepsilon and PU.1 Blood, April 15, 2003; 101(8): 3265 - 3273. [Abstract] [Full Text] [PDF] |
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H. Hirai Molecular Mechanisms of Myelodysplastic Syndrome Jpn. J. Clin. Oncol., April 1, 2003; 33(4): 153 - 160. [Abstract] [Full Text] [PDF] |
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J. Cammenga, J. C. Mulloy, F. J. Berguido, D. MacGrogan, A. Viale, and S. D. Nimer Induction of C/EBPalpha activity alters gene expression and differentiation of human CD34+ cells Blood, March 15, 2003; 101(6): 2206 - 2214. [Abstract] [Full Text] [PDF] |
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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] |
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B.-T. H. Truong, Y.-J. Lee, T. A. Lodie, D. J. Park, D. Perrotti, N. Watanabe, H. P. Koeffler, H. Nakajima, D. G. Tenen, and S. C. Kogan CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia Blood, February 1, 2003; 101(3): 1141 - 1148. [Abstract] [Full Text] [PDF] |
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J. Rangatia, R. K. Vangala, N. Treiber, P. Zhang, H. Radomska, D. G. Tenen, W. Hiddemann, and G. Behre Downregulation of c-Jun Expression by Transcription Factor C/EBP{alpha} Is Critical for Granulocytic Lineage Commitment Mol. Cell. Biol., December 15, 2002; 22(24): 8681 - 8694. [Abstract] [Full Text] [PDF] |
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C. Preudhomme, C. Sagot, N. Boissel, J.-M. Cayuela, I. Tigaud, S. de Botton, X. Thomas, E. Raffoux, C. Lamandin, S. Castaigne, 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, September 26, 2002; 100(8): 2717 - 2723. [Abstract] [Full Text] [PDF] |
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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, July 18, 2002; 100(3): 998 - 1007. [Abstract] [Full Text] [PDF] |
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