scholarly journals Differential effects of sumoylation on the activities of CCAAT enhancer binding protein alpha (C/EBPa) p42 versus p30 may contribute in part, to aberrant C/EBPa activity in acute leukemias

2011 ◽  
Vol 3 (1) ◽  
pp. 5 ◽  
Author(s):  
William Hankey ◽  
Matthew Silver ◽  
Hong Sun ◽  
Terry Zibello ◽  
Nancy Berliner ◽  
...  
Keyword(s):  
Binding Protein ◽  
Acute Leukemias ◽  
Differential Effects ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

Differential Transactivation Activities of Sumoylated CCAAT Enhancer Binding Protein alpha (C/EBPα) p42 Versus p30 May Contribute in Part, to Aberrant C/EBPα Activity in Acute Leukemias.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1231-1231
Author(s):  
Arati Khanna-Gupta ◽  
Matthew Silver ◽  
William Hankey ◽  
Hong Sun ◽  
Nancy Berliner
Keyword(s):  
Leucine Zipper ◽  
Binding Protein ◽  
Myeloid Cells ◽  
Leukemic Cell ◽  
Dominant Negative ◽  
Acute Leukemias ◽  
Leukemic Cell Lines ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Immature Myeloid Cells

Abstract CCAAT enhancer binding protein alpha (C/EBPα) is the founding member of a family of basic region/leucine zipper (bzip) transcription factors and has been shown to be a master regulator of granulopoiesis It is expressed at high levels throughout myeloid differentiation and has been shown to bind to the promoters of multiple myeloid- specific genes at different stages of myeloid maturation. Profound hematopoietic abnormalities have been reported for mice nullizygous for C/EBPα, including a selective early block in the differentiation of granulocytes. Recently mutations in C/EBPα have been demonstrated in a subset of patients with AML presenting normal karyotypes. These mutations can result in the expression of a 30kD dominant negative C/EBPα isoform which contributes to loss of C/EBPα function. Since the molecular basis for this observation remains unknown, a complete understanding of the regulation of this key transcription factor during myelopoiesis is critical. C/EBPα was recently shown to be post-translationally modified by small ubiquitin-related modifier (SUMO) at a lysine residue (K159) which lies within a region of the C/EBPα protein that can negatively affect transcriptional activity. Sumoylation at K159 in the C/EBPα protein is thought to prevent association of the SWI/SNF chromatin remodeling complex with C/EBPα, thereby hampering transactivation. In order to demonstrate the role of sumoylation in mediating C/EBPα activity, we examined the effect of both the full length (p42) and the dominant negative (p30) isoforms of the C/EBPα protein on myeloid gene expression. We demonstrate that the levels of sumoylated p42C/EBPα decrease upon normal neutrophil maturation, and that transactivation of the myeloid-specific lactoferrin promoter reporter is significantly enhanced by a p42 sumoylation mutant of C/EBPα (K159A). Additionally, in oligonucleotide pull down assays, we show that sumoylated p42C/EBPα binds to the C/EBP site in the LF promoter in immature myeloid cells while loss of sumoylation correlates with loss of p42C/EBPα binding and LF expression in more mature cells. Based on these observations we conclude that sumoylated p42C/EBPα is associated with the negative regulation of LF in early myeloid cells. We show in addition, that p30 C/EBPα can also be sumoylated. In transactivation assays, however, sumoylated p42C/EBPα suppresses LF promoter activity more efficiently than p30C/EBPα in 293 cells. We are now in the process of confirming this finding in leukemic cell lines. This observation leads us to hypothesize that the differential transactivation potential of sumoylated p30 versus the p42 C/EBPα proteins may contribute, in part, to the aberrant activity of C/EBPα in acute leukemias.

scholarly journals Dysregulation of CCAAT/enhancer binding protein-alpha (CEBPA) expression in the bone marrow of acute myeloid leukemia patients

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Naglaa M. Hassan ◽  
Fadwa Said ◽  
Roxan E. Shafik ◽  
Mona S. Abdellateif
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Binding Protein ◽  
Response To Treatment ◽  
Pathological Features ◽  
Poor Prognostic Factor ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous malignant disease characterized by accumulation of different types of mutations commonly the CCAAT/enhancer binding protein-alpha (CEBPA). However, the dysregulations of CEBPA expression in AML is still a debatable issue. The aim of the current study was to assess CEBPA gene expression in bone marrow (BM) aspiration specimens of 91 AML patients, compared to 20 control donors of bone marrow transplantation (BMT), using RT-PCR. Data were correlated with patients’ clinico-pathological features, response to treatment, progression-free survival (PFS), and overall survival (OS) rates. Results There was overexpression of CEBPA gene in AML patients compared to normal control [1.7 (0.04–25.6) versus 0.17 (0–4.78), respectively, P < 0.001]. Upregulation of CEBPA expression associated significantly with increased BM hypercellularity, total leucocyte counts, peripheral blood blast cell count, and poor PFS (P < 0.001, 0.002, 0.001, and 0.013, respectively). There was no significant association between CEBPA expression and any other relevant clinico-pathological features or OS rates (P = 0.610) of the patients. ROC analysis for biological relevance of CEBPA expression with AML showed that sensitivity and specificity of CEBPA expression at a cut-off value of 0.28 are 92.3% and 78.6%, respectively (P < 0.001). All patients who had CEBPA overexpression and mutant FLT3 showed BM hypercellularity, adverse cytogenetic risk, increased TLC, and PB blast cells count (P = 0.007, P < 0.001, 0.016, and 0.002, respectively). Conclusion CEBPA overexpression could be used as a genetic biological marker for AML diagnosis, as well as a poor prognostic factor for disease progression. It has no impact on OS rates of the patients.

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