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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1332-1340
NEOPLASIA
Mutations in the gene encoding the transcription factor
CCAAT/enhancer binding protein  in myelodysplastic syndromes and
acute myeloid leukemias
Adrian F. Gombart,
Wolf-K. Hofmann,
Seiji Kawano,
Seisho Takeuchi,
Utz Krug,
Scott H. Kwok,
Renee J. Larsen,
Hiroya Asou,
Carl W. Miller,
Dieter Hoelzer, and
H.
Phillip Koeffler
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  (C/EBP) protein is
essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that
abnormalties in C/EBP function contribute to the development of
malignancies in a variety of tissues. To test this, genomic DNA from
408 patient samples and 5 cell lines representing 11 different cancers
was screened for mutations in the C/EBP gene. Two silent
polymorphisms termed P1 and P2 were present at frequencies of 13.5%
and 2.2%, respectively. Of the12 mutations detected in 10 patients,
silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelogenous leukemia (AML) subtype M4.
The 9 remaining mutations were detected in 1 of 92 (1.1%) myelodysplastic syndrome (MDS) samples and 6 of 78 (7.7%) AML (AML-M2
and AML-M4) samples. Some mutations truncated the predicted protein
with loss of the DNA-binding (basic region) and dimerization (leucine
zipper [ZIP]) domains by either deletions or nonsense codons. Also,
inframe deletions or insertions in the fork region located between the
leucine zipper and basic region, or within the leucine zipper,
disrupted the -helical phase of the bZIP domain. The inframe
deletion and insertion mutations abrogated the transcriptional
activation function of C/EBP on the granulocyte colony-stimulating
factor receptor promoter. These mutants localized properly to
the nucleus, but were unable to bind to the C/EBP site in the promoter
and did not possess dominant-negative activity. The mutations in the
MDS patient and one AML-M2 patient were biallelic, indicating a loss of
C/EBP function. These results suggest that mutation of C/EBP is
involved in specific subtypes of AML and in MDS, but may occur rarely
in other types of leukemias or nonhematologic malignancies.
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|
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|
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108(4):
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|
|
|
|
|
|
|
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107(11):
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|
|
|
|
|
|
|
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107(11):
4308 - 4316.
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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
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20(5):
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[Full Text]
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|
|
|
|
|
|
|
Y. Tada, R. M. Brena, B. Hackanson, C. Morrison, G. A. Otterson, and C. Plass
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98(6):
396 - 406.
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|
|
|
|
|
|
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February 21, 2006;
203(2):
371 - 381.
[Abstract]
[Full Text]
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|
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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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
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J. Exp. Med.,
July 5, 2005;
202(1):
85 - 96.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Gombart, N. Borregaard, and H. P. Koeffler
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July 1, 2005;
19(9):
1067 - 1077.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
T. Ikezoe, S. Gery, D. Yin, J. O'Kelly, L. Binderup, N. Lemp, H. Taguchi, and H. P. Koeffler
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June 1, 2005;
65(11):
4762 - 4768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
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