The emergence of a C/EBPα mutation in the clonal evolution of MDS towards secondary AML

Kaeferstein, A; Krug, Utz; Tiesmeier, Jens; Aivado, Manuel; Faulhaber, Marion; Stadler, Michael; Krauter, Juergen; Germing, Ulrich; Hofmann, Werner; Koeffler, H. Phillip; Ganser, Arnold; Verbeek, Walter

doi:10.1038/sj.leu.2402805

Cited by 34 publications

(33 citation statements)

References 24 publications

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“…C/EBPA mutations were first described by Pabst et al in 2001 [9], and have subsequently been observed by many other investigators with the frequency of 5-14% in de novo AML [5][6][7][8][9]. The gene mutation is composed of base pair substitutions, deletions, and insertions and can be largely divided into two common types: First, carboxy-terminal in-frame mutations which disrupt the basic zipper region, thus affecting DNA binding as well as homodimerization and heterodimerization with other C/EBP family members.…”

Section: Introductionmentioning

confidence: 90%

“…Growing evidence indicates that the key function of C/EBPA gene can be altered by a number of mechanisms, such as gene mutation, transcriptional dysregulation, as well as epigenetic modification in leukemic cells of AML patients, and the functional inactivation of C/EBPA has become a pathophysiological signature of myeloid leukemia. The events leading to the loss of C/EBPA function facilitate leukemogenesis by blocking granulocytic differentiation in hematopoiesis of AML patients [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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C/EBPA gene mutation and C/EBPA promoter hypermethylation in acute myeloid leukemia with normal cytogenetics

Chen

et al. 2010

American J Hematol

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In the current study, we investigated C/EBPA gene mutations and promoter hypermethylation in a series of 53 patients with CN-AML. In addition, we also analyzed two other frequent mutations (FLT3/ITD and NPM1) in these patients and correlated them with C/EBPA gene alterations. 13/53 patients were FLT3/ITD1/NPM1-, 11/53 patients were FLT3/ITD1/NPM11, 9/53 patients were FLT3/ITD-/NPM11, and 20/53 patients were FLT3/ITD-/NPM1-. Four of 53 cases displayed C/EBPA mutations, whereas 49 cases had only C/EBPA wildtype alleles. Of the four positive cases, three patients had N-terminal mutations only, whereas one patient had mutations in both the N-and C-terminal region. Two of the four positive cases also harbored both FLT3/ITD and NPM1 mutation simultaneously, whereas the other two patients had neither FLT3/ITD nor NPM1 mutations. Furthermore, 7/53 cases displayed C/EBPA promoter hypermethylation. Interestingly, they were all in CN-AML cases without FLT3/ITD or NPM1 mutations. None of the seven patients with C/EBPA promoter hypermethylation showed C/EBPA mutation. In conclusion, C/EBPA mutation and promoter hypermethylation can be detected at a relatively low frequency in de novo CN-AML patients, suggesting they may contribute to leukemogenesis. C/EBPA mutation appears to be seen in ''high-risk'' AML (FLT3/ITD1/NPM11; FLT3/ITD1/NPM1-or FLT3/ITD-/NPM1-), while C/EBPA hypermethylation appears to be more common in AML with FLT3/ITD-/NPM1-and is not associated with C/EBPA mutation. Am. J. Hematol. 85:426-430, 2010. V

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Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

C/EBPA gene mutation and C/EBPA promoter hypermethylation in acute myeloid leukemia with normal cytogenetics

Chen

et al. 2010

American J Hematol

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“…153 Acquired point mutations of the CEBPA gene have been reported in 89 of 965 (9%) AML patients in 7 studies including 12 M0-AML, 159 M1-AML, 203 M2-AML, 44 M3-AML, 101 M4-AML, 98 M5-AML, 8 M6-AML, 4 M7-AML and 15 secondary AML and 321 AML for which FAB or WHO classification was not mentioned. 146,[153][154][155][156][157][158][159][160] CEBPA mutations can be divided into two main groups: N-terminal mutations that lead to increased translation of the alternative 30-kDa form with dominant-negative activity on the full-length 42-kDa protein; and C-terminal mutations that result in deficient DNA-binding and/or homodimerization activities. Some patients present a single CEBPA mutation, while some others have multiple alterations resulting from biallelic mutations or from several mutations on the same allele.…”

Section: Cebpamentioning

confidence: 99%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

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“…Finally, inactivating CEBPA mutations have been reported in hematological malignancies, especially in AML. 3,[20][21][22][23][24][25][26] In this review, we focused on CEBPA mutations and how, through inactivation of transcriptional properties of the CEBPA protein, they could lead to leukemogenesis.…”

Section: Introductionmentioning

confidence: 99%

CEBPA point mutations in hematological malignancies

et al. 2005

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The CCAAT/enhancer-binding protein-alpha (CEBPA) is a transcription factor strongly implicated in myelopoiesis through control of proliferation and differentiation of myeloid progenitors. Recently, several works have reported the presence of CEBPA-acquired mutations in hematological malignancies. In this work, we analyzed characteristics of mutations and their correlation with disease characteristics described in previous studies. In the 1175 patients reported, 146 CEBPA mutations were identified in 96 patients. Mutations were found in the whole gene sequence, but cluster regions were clearly identified. Furthermore, two categories of mutations were reported: out-of-frame ins/del often in the N-terminal region, and in-frame ins/del often in the C-terminal region. CEBPA mutations were reported exclusively in acute myeloid leukemia (AML) (according to WHO classification criteria) and mutated patients preferentially belonged to M1, M2 and M4 FAB subtypes. All but one case belonged to the 'intermediate' prognostic subgroup of MRC classification. In the absence of poor prognostic factors, patients with CEBPA mutation had favorable outcome, very similar to that of the t(8;21), inv(16), t(15;17) subgroup. Systematic analysis of CEBPA mutations, in addition to that of alterations in master genes of hematopoiesis, may be useful to assess the prognosis of AML particularly in patients belonging to the 'intermediate' prognostic subgroup.

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The emergence of a C/EBPα mutation in the clonal evolution of MDS towards secondary AML

Cited by 34 publications

References 24 publications

C/EBPA gene mutation and C/EBPA promoter hypermethylation in acute myeloid leukemia with normal cytogenetics

C/EBPA gene mutation and C/EBPA promoter hypermethylation in acute myeloid leukemia with normal cytogenetics

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

CEBPA point mutations in hematological malignancies

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