CEBPA gene mutations in Egyptian acute myeloid leukemia patients: impact on prognosis
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To assess the prognostic role of myeloid transcription factor gene CEBPA (CCAAT/enhancer binding protein-α), a novel gene involved in leukemia in Egyptian adults AML.Screening for CEBPA mutations was assessed using PCR-single-strand conformation polymorphism (PCR-SSCP) in pretreatment bone marrow samples from 55 newly diagnosed adult AML.CEBPA mutations were found in 11 (20%) of 55 AML patients. They had significantly higher hemoglobin (P = 0.037), and lower LDH (P = 0.003) levels when compared to those without. CEBPA mutations were frequently detected in M4 (45.5%) and M2 (27.2%) subtypes, and significantly associated with normal karyotype (90.9%, P = 0.007). We distinguished six cases with two different mutations or one homozygous mutation (CEBPA(double-mut)) as well as five cases with only one single heterozygous mutation (CEBPA(single-mut)). Patients with CEBPA mutations had significantly higher complete remission (P = 0.047), lower mortality (p = 0.047). Double CEBPA mutant cases showed longer disease free survival (DFS) and overall survival (OS) when compared to wild type CEBPA (for DFS; median = 27 versus 24 months respectively; P = 0.009 and for OS; median = 28 versus 25 months respectively; p = 0.008). No significant differences were found between CEBPA(single-mut) cases and wild type cases regarding DFS and OS (for DFS; median = 13 versus 24 months respectively; P = 0.615 and for OS; median = 14 versus 25 months respectively; P = 0.703).CEBPA mutation status is known to be a prognostic factor for favorable outcome in AML patients. CEBPA(double-mut) is associated with favorable DFS and OS. In contrast, CEBPA(single-mut) AMLs survival studies did not differ significantly with wild-type cases. These results demonstrate significant underlying heterogeneity within CEBPA mutation positive AML with prognostic relevance. Based on these findings, we propose that CEBPA(double-mut) should be clearly defined from CEBPA(single-mut) AML and considered as a separate entity in the classification of AML. Furthermore, incorporation of CEBPA mutation status into novel risk-adapted therapeutic strategies in Egypt will improve the currently disappointing cure rate of this group of patients.Keywords:
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Objective:To explore the possibility of secondary neoplasia following long term combined chemotherapy.Methods:Sister chromatid exchanges(SCE)were investigated in 44 patients with adult leukemia.Rusults:Frequencies of SCE in patients with de novo leukemia,relapsed leukemia and chronic myeloid leukemia(CML)were significant higher than health controls.The five patients(5/16)with complete remission showed higher SCE frequencies,those were mainly the patients received more than nine courses of combined chemotherapeutic regimens received more than nine courses of combined chemotherapeutic regimens.Conclusion:The patients with de novo leukemia,relapsed leukemia and CML have DNA damage in diagnosis,long term combined chemotherapy may cause the DNA instability in partial patients.
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Abstract C/EBPα is expressed preferentially in myeloid compared with lymphoid or erythroid cells and directs myeloid lineage specification. C/EBPα is also expressed at lower levels in HSCs and in several nonhematopoietic tissues. The Cebpa gene has a conserved, 450-bp segment at +37 kb that harbors enhancer-specific epigenetic marks and is activate in a myeloid cell line. Herein, we characterize transgenic C57BL/6 mice, in which the Cebpa enhancer and 845-bp promoter regulate a hCD4 reporter. FACS analysis, in vitro colony assays, and in vivo competitive and secondary transplantation revealed that myeloid but not MEPs or lymphoid progenitors and also functional LT-HSCs are found almost exclusively in the Cebpa-hCD4+ compared with hCD4− marrow population. hCD4+ CMP yielded predominantly myeloid, whereas hCD4− CMP generated mainly Meg/E colonies. Providing insight into control of CMP maturation, Cebpa and Pu.1 RNAs were preferentially expressed in hCD4+ CMP, Scl, Gata2, Gata1, Klf1, Ets1, and Fli1 predominated in hCD4− CMP, and Runx1, Myb, HoxA9, and Erg levels were similar in both. Cebpa-hCD4 transgene expression was lacking in multiple nonhematopoietic tissues. In summary, the +37-kb Cebpa enhancer and promoter are sufficient for marrow myeloid progenitor and LT-HSC-specific expression.
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Both acute myeloid leukemia 1 and c‐Fos are regulatory factors of hematopoietic cell differentiation. We identified that the c‐fos promoter contains an acute myeloid leukemia 1 binding site at nucleotide positions −6–+14. c‐fos promoter activity was induced by transient overexpression of acute myeloid leukemia 1 in Jurkat T‐cells, but not by that of the short form of acute myeloid leukemia 1‐MTG8, a chimeric acute myeloid leukemia 1 protein. In 32Dcl3 myeloid cells, stable overexpression of acute myeloid leukemia 1‐MTG8 blocked the c‐fos gene transcription and cell differentiation, but that of acute myeloid leukemia did not. These data suggest that acute myeloid leukemia 1 and acute myeloid leukemia 1‐MTG8 reciprocally regulate the myeloid cell differentiation, possibly by the way of regulating c‐fos gene transcription.
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We examined the gene expression profiles of two independent cohorts of patients with acute myeloid leukemia [n=247 and n=214 (younger than or equal to 60 years)] to study the applicability of gene expression profiling as a single assay in prediction of acute myeloid leukemia-specific molecular subtypes. The favorable cytogenetic acute myeloid leukemia subtypes, i.e., acute myeloid leukemia with t(8;21), t(15;17) or inv(16), were predicted with maximum accuracy (positive and negative predictive value: 100%). Mutations in NPM1 and CEBPA were predicted less accurately (positive predictive value: 66% and 100%, and negative predictive value: 99% and 97% respectively). Various other characteristic molecular acute myeloid leukemia subtypes, i.e., mutant FLT3 and RAS, abnormalities involving 11q23, −5/5q-, −7/7q-, abnormalities involving 3q (abn3q) and t(9;22), could not be correctly predicted using gene expression profiling. In conclusion, gene expression profiling allows accurate prediction of certain acute myeloid leukemia subtypes, e.g. those characterized by expression of chimeric transcription factors. However, detection of mutations affecting signaling molecules and numerical abnormalities still requires alternative molecular methods.
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AMA Pieronkiewicz M, Lewandowski K. Prognostic significance of CEBPA gene mutations in patients with acute myeloid leukemia. Contemporary Oncology/Współczesna Onkologia. 2010;14(6):363-371. doi:10.5114/wo.2010.19151. APA Pieronkiewicz, M., & Lewandowski, K. (2010). Prognostic significance of CEBPA gene mutations in patients with acute myeloid leukemia. Contemporary Oncology/Współczesna Onkologia, 14(6), 363-371. https://doi.org/10.5114/wo.2010.19151 Chicago Pieronkiewicz, Marzena, and Krzysztof Lewandowski. 2010. "Prognostic significance of CEBPA gene mutations in patients with acute myeloid leukemia". Contemporary Oncology/Współczesna Onkologia 14 (6): 363-371. doi:10.5114/wo.2010.19151. Harvard Pieronkiewicz, M., and Lewandowski, K. (2010). Prognostic significance of CEBPA gene mutations in patients with acute myeloid leukemia. Contemporary Oncology/Współczesna Onkologia, 14(6), pp.363-371. https://doi.org/10.5114/wo.2010.19151 MLA Pieronkiewicz, Marzena et al. "Prognostic significance of CEBPA gene mutations in patients with acute myeloid leukemia." Contemporary Oncology/Współczesna Onkologia, vol. 14, no. 6, 2010, pp. 363-371. doi:10.5114/wo.2010.19151. Vancouver Pieronkiewicz M, Lewandowski K. Prognostic significance of CEBPA gene mutations in patients with acute myeloid leukemia. Contemporary Oncology/Współczesna Onkologia. 2010;14(6):363-371. doi:10.5114/wo.2010.19151.
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