CEBPA polymorphisms and mutations in patients with acute myeloid leukemia, myelodysplastic syndrome, multiple myeloma and non-Hodgkin's lymphoma

Fuchs, Ota; Provazníková, Dana; Kocova, Marcela; Kostecka, Arnost; Cvekova, Pavla; Neuwírtová, R; Kobylka, Petr; Čermák, Jaroslav; Březinová, Jana; Schwarz, Jiřı́; Marková, Jana; Salaj, Peter; Klamová, Hana; Maaloufová, Jacqueline; Lemez, P; Nováková, Ludmila; Benešová, Kateřina

doi:10.1016/j.bcmd.2007.11.005

Cited by 40 publications

(43 citation statements)

References 21 publications

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“…We identified 3 types of polymorphisms including nt1175_ 1180dup, nt1281G>T and nt1401C>T. The nt1175_1180dup and nt1281G>T polymorphisms had been reported in previous studies [16][17][18][19] whereas nt1401C>T is a novel polymorphism. The most common type of polymorphism was the nt1175_1180dup which led to a histidine-proline duplication in the TAD2 domain.…”

Section: Discussionmentioning

confidence: 83%

“…12,[16][17][18][19][20][21][22][23][24][25][26] In this study, CEBPA mutations were found in 34 cases of 247 cases (13.8%) of Southeast Asian AML, the frequency of which was comparable to that of Taiwan (13-15%), 16,17,26 Germany (14%), 18,21,22 Switzerland (17.9%) 23 and France (11%), 24 but was slightly higher than that of the Czech Republic (9.2%), 18 the United States (7.3%) 12 and The Netherlands (6%). 25 Our study represents the first series reported from the ethnically distinct Southeast Asian region and is one of the largest series ever reported with respect to the CEBPA polymorphisms and mutations.…”

Section: Discussionmentioning

confidence: 99%

“…1 Previously reported mutations or polymorphisms. [15][16][17][18][19] were also found in M4 (25%), M2 (22.8%), M3 (21.8%), M1 (20.8%) and M0 (14.3%), respectively. One out of 2 M6 patients also had the CEBPA polymorphism.…”

Section: Incidence and Type Of Cebpa Coding Region Polymorphisms In Amlmentioning

confidence: 99%

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CCAAT/enhancer binding protein‐alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes

Leecharendkeat

Tocharoentanaphol

Auewarakul

2008

Intl Journal of Cancer

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CCAAT/enhancer binding protein-alpha (CEBPA) belongs to a family of leucine zipper transcription factors necessary for late differentiation events of many cell types. CEBPA gene has recently been recognized as the target of genetic alterations in acute myeloid leukemia (AML). CEBPA mutations and polymorphisms were determined in a large series of Southeast Asian AML (n = 247) using polymerase chain reaction and direct sequencing. Chromosome and FLT3 mutation analyses were also undertaken. Thirtytwo distinct types of nucleotide changes (7 known and 25 novel mutations) were identified in 34 cases (13.8%). Three types of polymorphisms were found in 60 cases (24.3%) including a novel nt1401C>T polymorphism. All polymorphisms were located at the C-terminal region whereas the majority of mutations (62.5%) occurred at the N-terminal region. The most common polymorphism was the nt1175_1180dup resulting in the predicted P194_H195 duplication protein in 50 cases. Although CEBPA mutations were predominantly associated with a normal karyotype (76%), 15.7% of patients with an unfavorable risk and 4.3% of patients with a favorable risk also had the mutations. Moreover, CEBPA polymorphisms were similarly found across all cytogenetic risk groups and occurred in all leukemia subtypes. FLT3 mutations were comparably discovered among patients with CEBPA mutations, polymorphisms and wild-type (26-30%). In conclusion, CEBPA polymorphisms occurred more frequently than CEBPA mutations and could be identified across all prognostic risk groups. The high occurrence of CEBPA polymorphisms should be recognized in order not to include this group of patients with CEBPA polymorphisms for prognostic evaluation of CEBPA mutations in any clinical trials.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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CCAAT/enhancer binding protein‐alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes

Leecharendkeat

Tocharoentanaphol

Auewarakul

2008

Intl Journal of Cancer

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“…35 Regarding MM, CEBPA polymorphism has been described in 5% of MM patients. 36 The 8p12-p23.3 MDR contains STAT1, which is a promoter of apoptosis required for interferon-alpha-mediated cell death, 37 and two proapoptotic molecules, TNFRSF10A, which transduces cell death signal and induces cell apoptosis, and BNIP3L that may function as a tumor suppressor. [38][39][40][41][42] On the other hand, the MGR at 8q22.2-q22.3, 16p12.1, 16p11.2 and 20q11.2, and the MDR at 2q35, 11p11.2, 12q24.11 and 14q11.2 detected in our series have not been described before.…”

Section: %mentioning

confidence: 99%

SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status

et al. 2012

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Genetic events mediating transformation from premalignant monoclonal gammopathies (MG) to multiple myeloma (MM) are unknown. To obtain a comprehensive genomic profile of MG from the early to late stages, we performed high-resolution analysis of purified plasma cells from 20 MGUS, 20 smoldering MM (SMM) and 34 MM by high-density 6.0 SNP array. A progressive increase in the incidence of copy number abnormalities (CNA) from MGUS to SMM and to MM (median 5, 7.5 and 12 per case, respectively) was observed (P ¼ 0.006). Gains on 1q, 3p, 6p, 9p, 11q, 19p, 19q and 21q along with 1p, 16q and 22q deletions were significantly less frequent in MGUS than in MM. Although 11q and 21q gains together with 16q and 22q deletions were apparently exclusive of MM status, we observed that these abnormalities were also present in minor subclones in MGUS. Overall, a total of 65 copy number-neutral LOH (CNN-LOH) were detected. Their frequency was higher in active MM than in the asymptomatic entities (P ¼ 0.047). A strong association between genetic lesions and fragile sites was also detected. In summary, our study shows an increasing genomic complexity from MGUS to MM and identifies new chromosomal regions involved in CNA and CNN-LOH.

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“…Samples from two patients had a TAD2 (1175 to 1180dup: ϩ6 bp) insertion previously reported as a polymorphism. 9,12,13 One polymorphism (patient G2) was initially detected only by fragment analysis. That case was classified as wild-type without a polymorphism by initial sequencing analysis, but the polymorphism was confirmed after sequencing more colonies.…”

Section: Characterization Of Cebpa Mutationsmentioning

confidence: 99%

A Comparison of Two Methods for Screening CEBPA Mutations in Patients with Acute Myeloid Leukemia

Ahn

Seo

Weinberg

et al. 2009

The Journal of Molecular Diagnostics

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The goal of the study was to compare the performance of a fluorescence-based multiplex PCR fragment analysis to a direct sequencing method for detecting CEBPA mutations in patients with acute myeloid leukemia. Thirty-three samples were selected from a larger study of 107 cases of acute myeloid leukemia by screening for CEBPA mutations by sequence analysis. Of ten identified mutations , six (insertions and deletions) were detected by both sequencing and fragment methods. The fragment analysis method did not detect the remaining four base substitutions because the method cannot detect changes that result in identically sized products. The multiplex PCR fragment length analysis method therefore failed to detect substitution mutations accounting for 40% of total CEBPA mutations in our patient set. Our results indicate that fragment length analysis should not be used in isolation , and that direct sequencing is required to evaluate CEBPA gene mutational status in acute myeloid leukemia. A combination of the two assays may offer some advantages , chiefly in permitting more sensitive detection by fragment length analysis of insertions and deletions. CEBPA encodes a protein exclusively expressed in the myelomonocytic lineage. It is important for commitment to the granulocytic lineage and for differentiation of mature neutrophils. 1 The ability of CEBPA to induce granulocytic differentiation is enhanced by RAS-dependent phosphorylation of serine 248 of the CEBPA transactivation domain. 2 Leukemia-associated CEBPA gene mutations can be divided into two groups. One group of mutations consists of in-frame insertions in the basic/ leucine zipper (bZIP) region that contains DNA-binding as well as dimerization domains. The other group of mutations consists of truncating out-of-frame insertions or deletions in the N-terminus, resulting in premature termination of the normal 42-kDa protein. 3 Most of the frameshifting N-terminal mutations cause enhanced translation of a dominant-negative 30-kDa protein, which may be responsible for the differentiation block observed in acute myeloid leukemias expressing this protein. 3 Mutations in the CEBPA gene are among the most common mutations in AML, particularly in patients with French-American-British (FAB) subtypes M1 and M2. 4 -6 The majority of leukemias with CEBPA mutations have a normal karyotype. 7,8 Several studies of the prognostic significance of CEBPA mutations in patients with acute myeloid leukemia (AML) have shown that the presence of a CEBPA mutation is associated with significantly increased event-free survival, overall survival, and remission duration. 2,6,7 In addition, sequential analysis of CEBPA mutations revealed that the same mutation was present at diagnosis and relapse, but not in complete remission. 4,9 Accurate testing for CEBPA mutations is important for identification of this prognostically significant AML subtype. AML with mutated CEBPA is a provisional disease entity in the 2008 World Health Organization classification of leukemias. 10 Many prior studies h...

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CEBPA polymorphisms and mutations in patients with acute myeloid leukemia, myelodysplastic syndrome, multiple myeloma and non-Hodgkin's lymphoma

Cited by 40 publications

References 21 publications

CCAAT/enhancer binding protein‐alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes

CCAAT/enhancer binding protein‐alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes

SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status

A Comparison of Two Methods for Screening CEBPA Mutations in Patients with Acute Myeloid Leukemia

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