Disease relevance of CEBPA

• Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA) [1].
• These results identify CEBPA as a key target of the leukemic fusion protein AME and suggest that modulation of CEBPA by CRT may represent a mechanism involved in the differentiation block in AME leukemias [2].
• Recently, several works have reported the presence of CEBPA-acquired mutations in hematological malignancies [3].
• Overexpression of CEBPA resulting from the translocation t(14;19)(q32;q13) of human precursor B acute lymphoblastic leukemia [4].
• Mutations of the myeloid transcription factor CEBPA are not associated with the blast crisis of chronic myeloid leukaemia [5].
• In concordance with these results, CDDO induces a CEBPA ratio change and differentiation of primary blasts from patients with acute myeloid leukemia (AML) [6].

High impact information on CEBPA

• Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia [7].
• Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and no mature granulocytes are observed in Cebpa-mutant mice [7].
• In addition, we detected no differences in CEBPA mRNA levels in leukemic blasts of patients carrying the AME translocation (n = 8) compared to acute myeloid leukemia patients with a normal karyotype (n = 9) [2].
• A recurrent in-frame insertion in a CEBPA transactivation domain is a polymorphism rather than a mutation that does not affect gene expression profiling-based clustering of AML [8].
• The CEBPA protein is known to regulate the balance between cell proliferation and differentiation during early hematopoietic development and myeloid differentiation [4].

Biological context of CEBPA

• CEBPA mutations were present only in patients belonging to the intermediate cytogenetic risk subgroup and associated with the FAB-M1 subtype (P =.02) [1].
• PURPOSE: To assess the prognostic relevance of mutations in the CEBPA gene encoding CCAAT/enhancer binding protein alpha (C/EBP alpha) in a large prospective series of younger adults with acute myeloid leukemia (AML) and normal cytogenetics [9].
• The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin [2].
• 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 [3].
• The CCAAT/enhancer-binding protein-alpha (CEBPA) is a transcription factor strongly implicated in myelopoiesis through control of proliferation and differentiation of myeloid progenitors [3].

Anatomical context of CEBPA

• Here, we found that conditional expression of core-binding factor beta (CBFB)-SMMHC in U937 cells suppresses CEBPA protein expression and binding activity [10].
• The transcription factor C/EBPalpha (for CCAAT/enhancer binding protein-alpha; encoded by the gene CEBPA) is crucial for the differentiation of granulocytes [7].
• Furthermore, we observed that calreticulin (CRT), a putative inhibitor of CEBPA translation, was strongly activated after induction of AME in the cell-line system (14.8-fold) and in AME patient samples (12.2-fold) [2].
• NPM mutations were detected in 47% of patients and were associated with a high white blood cell count, involvement of the monocytic lineage (M4/M5), and a decreased prevalence of CEBPA mutations [11].
• We report that CEBPA is activated by juxtaposition to the immunoglobulin gene enhancer upon its rearrangement with the immunoglobulin heavy-chain locus in precursor B-cell acute lymphoblastic leukemia harboring t(14;19)(q32;q13) [4].

Associations of CEBPA with chemical compounds

• CCAAT enhancer-binding protein alpha suppresses the rat placental glutathione S-transferase gene in normal liver [12].
• Indeed, anandamide induced triglyceride droplet accumulation and the expression of PPARgamma responsive genes such as CCAAT enhancer binding protein alpha (C-EBPalpha), aP2, PerilipinA and Acrp30 [13].
• FAA treatment also causes a subsequent induction of the proapoptotic CHOP (CEBP homologous protein) transcription factor as well as a late activation of caspase-12 [14].
• Thapsigargin suppresses phorbol ester-dependent human involucrin promoter activity by suppressing CCAAT-enhancer-binding protein alpha (C/EBPalpha) DNA binding [15].

Physical interactions of CEBPA

• In this paper, we present a mutant that disrupts a hepatocyte-nuclear-factor-3/CCAAT-enhancer binding protein alpha binding site in the CYP3A4 proximal promoter [16].
• Sequence analysis of the resistin promoter revealed several putative binding sites for adipogenic transcription factors including adipocyte determination- and differentiation-dependent factor 1 (ADD1)/sterol regulatory element binding protein 1c (SREBP1c) and CCAAT enhancer binding protein-alpha (C/EBP alpha) [17].
• Furthermore, sequence analysis identified multiple CCAAT enhancer binding protein alpha (C/EBPalpha) binding sites within the ORF 9 promoter and specifically two within the close vicinity of the AT-rich ORF 50 RE [18].

Regulatory relationships of CEBPA

• Long-acting beta2-agonists prime the glucocorticoid receptor and enhance nuclear translocation via activation of CCAAT enhancer binding protein-alpha [19].

Other interactions of CEBPA

• Inhibition of calreticulin by siRNA restored CEBPA levels [10].
• FLT3 internal tandem duplication (ITD) was found in 5 of 15 CEBPA-mutated as compared with 30 of 119 CEBPA-nonmutated cases tested (P =.54) [1].
• CONCLUSIONS: Assessment of CEBPA mutations, FLT3-ITD, and BAALC expression permits to split normal-karyotype AML into clinically distinct subgroups [20].
• CEBPA, PAX5 and PU1 were negative for all cell lines tested except in the three positive BCP-cell lines [21].
• NPM1 mutations associate inversely with the occurrence of CCAAT/enhancer-binding protein-alpha (CEBPA) and NRAS mutations [22].

Analytical, diagnostic and therapeutic context of CEBPA

• Median disease-free survival (DFS) and overall survival (OS) were 33.5 and 45.5 months, respectively, compared with 10 (e.g., 12 months in patients without CEBPA mutations; P = 0.0017; P = 0.0007) [20].
• There was no evidence for deletion of this region in the other six mutated samples analyzed by fluorescence in situ hybridization with a BAC clone spanning the CEBPA locus [23].
• A novel fluorescence-based multiplex PCR assay for rapid simultaneous detection of CEBPA mutations and NPM mutations in patients with acute myeloid leukemias [24].
• Further sequence analysis revealed that CEBPA C-terminal mutations are associated with frameshift mutations in the N-terminus of CEBPA [25].
• Despite unchanged CCAAT-enhancer binding protein alpha (C/EBPalpha) and increased C/EBPbeta levels, nuclear proteins of EGF-treated cells did not bind to a C/EBP DNA probe in a gel mobility shift assay [26].

References