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Regulation of the C/Ebpα Signaling Pathway in Acute Myeloid Leukemia (Review)

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Regulation of the C/Ebpα Signaling Pathway in Acute Myeloid Leukemia (Review) ONCOLOGY REPORTS 33: 2099-2106, 2015 Regulation of the C/EBPα signaling pathway in acute myeloid leukemia (Review) GUANHUA SONG1, LIn Wang2, Kehong BI3 and guosheng JIang1 1Department of hemato-oncology, Institute of Basic Medicine, shandong academy of Medical sciences, Key Laboratory for Modern Medicine and Technology of Shandong Province, Key Laboratory for Rare and Uncommon Diseases, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of shandong Province, Jinan, Shandong 250062; 2Research Center for Medical Biotechnology, Shandong Academy of Medical Sciences, Jinan, Shandong 250062; 3Department of Hematology, Qianfoshan Mountain Hospital of Shandong University, Jinan, Shandong 250014, P.R. China Received December 2, 2014; Accepted January 26, 2015 DoI: 10.3892/or.2015.3848 Abstract. The transcription factor CCAAT/enhancer binding Contents protein α (C/EBPα), as a critical regulator of myeloid devel- opment, directs granulocyte and monocyte differentiation. 1. Introduction Various mechanisms have been identified to explain how 2. Function of C/EBPα in myeloid differentiation C/EBPα functions in patients with acute myeloid leukemia 3. Regulation of the C/EBPα signaling pathway (AML). C/EBPα expression is suppressed as a result of 4. Conclusion common leukemia-associated genetic and epigenetic altera- tions such as AML1-ETO, RARα-PLZF or gene promoter methylation. Recent data have shown that ubiquitination modi- 1. Introduction fication also contributes to its downregulation. In addition, 10-15% of patients with AML in an intermediate cytogenetic Acute myeloid leukemia (AML) is characterized by uncon- risk subgroup were characterized by mutations of the C/EBPα trolled proliferation of myeloid progenitors that exhibit a gene. As a transcription factor, C/EBPα can translocate into severe block in their ability to differentiate into mature the nucleus and further regulate a variety of genes directly or granulocytes or macrophages (1). The transcription factor indirectly, which are all key factors for cell differentiation. This CCAAT/enhancer binding protein α (C/EBPα) is a lineage- review summarizes recent reports concerning the dysregula- specific transcription factor in the hematopoietic system and is tion of C/EBPα expression at various levels in human AML. required for the formation of committed myeloid progenitors The currently available data are persuasive evidence suggesting from multipotent precursor cells by coupling the direct tran- that impaired abnormal C/EBPα expression contributes to the scriptional activation of myeloid-specific genes with the arrest development of AML, and restoration of C/EBPα expression of cell proliferation (2). as well as its function represents a promising target for novel C/EBPα is specifically expressed in granulocytes, therapeutic strategies in AML. monocytes and eosinophils (3), although it is also found in hepatocytes, adipocytes and type II pneumocytes (4). Previous studies have illustrated the function of C/EBPα in hematopoiesis by promoting granulocyte and monocyte differ- entiation (2,5,6). Studies have eported that C/EBPα expression is detectable at a low level in the hematopoietic stem cell (HSC) Correspondence to: Dr Kehong Bi, Department of Hematology, population, and its expression increases as these cells develop Qianfoshan Mountain Hospital of Shandong University, Jingshi into the common myeloid progenitor (CMP) and subsequently Road, Jinan, Shandong 250014, P.R. China the granulocyte-monocyte progenitor (GMP), while condi- E-mail: [email protected] tional C/EBPα deficiency in adult mice blocked the transition from CMP to GMP, resulting in reduced formation of both Dr guosheng Jiang, Department of hemato-oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, 18877 granulocytes and monocytes (7). Non-conditional targeted Jingshi Road, Jinan, Shandong 250062, P.R. China disruption of C/EBPα was found to result in a selective block E-mail: [email protected] in early granulocyte maturation, and these mice died at birth due to severe hypoglycemia (8). Moreover, knock-in mice Key words: C/EBPα, leukemia, differentiation, granulocyte, with a targeted mutation in the C/EBPα basic region, which monocyte led to its dysfunction, predisposed the mice to a myelopro- liferative disorder (9). However, when expressed in 32Dcl3 2100 song et al: REGULaTION oF C/eBPα In aCuTe MYeLoID LEUKeMIa Figure 1. Structure of the two isoforms of C/EBPα. C/EBPα, CCAAT/enhancer binding protein α. cells, representative of granulocytic progenitors, exogenous studies have reported that C/EBPα heterodimerizes with AP-1 C/EBPα promoted granulopoiesis (10). These studies suggest proteins (C/EBPα:c-Jun or C/EBPα:-c-Fos) for preference in that C/EBPα is a critical regulator of myeloid development. In directing monopoiesis (17), whereas C/EBPα homodimers fact, growing evidence suggests that the function of C/EBPα is cooperate with NF-κB p50 to promote granulopoiesis (18). critically altered in subsets of AML patients based on various Regulation of macrophage and neutrophil cell fates may also factors. be altered by the relative PU.1:C/EBPα ratio (19). In this review, we summarized the fundamental role of C/EBPα in myeloid differentiation and the recently identified 3. Regulation of the C/EBPα signaling pathway mechanisms of its activity. As a critical factor involved in myeloid differentiation, the 2. Function of C/EBPα in myeloid differentiation function of C/EBPα must be tightly regulated to maintain the differentiation homeostasis. Detailed study of the regulation of C/EBPα is a member of the basic leucine zipper (bZIP) C/EBPα could also highlight the understanding of the patho- transcription factor family, of which several members are logical mechanisms of AML. also expressed in the myeloid lineage (e.g., C/EBPβ and C/EBPε) (2). In mammals, C/eBPα is a lineage-specific tran- Regulators targeting C/EBPα in myeloid differentiation and scription factor that is required for the formation of committed leukemogenesis. Many researches have focused on the factors myeloid progenitors from multipotent precursor cells. The regulating C/EBPα expression and its functions in leukemic C/EBPα molecule contains transactivation domains (TADs) diseases from different aspects, such as transcriptional at its n-terminus and a DNA-binding and dimerization bZIP repression by fusion genes, ubiquitination modification and structure at its C-terminus. Furthermore, C/EBPα is an intron- epigenetic regulation. less gene whose mRNA can be translated from two different Among the variant translocations in AML, the t(11:17) AUG codons giving rise to two distinct isoforms (p42 and p30). translocation is the most frequent, and renders resistance to p30 lacks two N-terminal transactivation domains that are all-trans retinoic acid (ATRA) treatment (20). After transloca- only present on p42 (11) (Fig. 1). Unless otherwise indicated, tion, RARα is fused to PLZF to produce two fusion proteins, C/EBPα represents the p42 isoform in the present review. promyelocytic eukemia zinc finger-retinoic acid receptor α To date, numerous studies have been reported regarding (PLZF-RARα) and RARα-PLZF, both of which participate the function of C/EBPα in AML. Firstly, genomic mutations in leukemia development (21). Among them, RARα-PLZF have been detected in the C/EBPα gene in ~5-14% of AML recruits HDAC1 and causes histone H3 deacetylation at patients (12,13). Among these mutations, N-terminal frame- C/EBPα target loci, thereby decreasing the expression of shift mutations prematurely truncate the full-length p42 form C/EBPα (Fig. 2). In line with this result, hDaC inhibitors were while preserving the p30 form, with the latter inhibiting the found to restore C/EBPα expression to a modest extent (22). remaining wild-type C/EBPα p42 protein in a dominant-nega- In addition to RaRα-PLZF, C/EBPα expression could also be tive manner (12). In addition, C-terminal in-frame insertions downregulated through direct transcriptional repression by the or deletions were found to disrupt the basic zipper region, thus fusion oncoprotein aML1-eTo (23). These findings provide critically affecting DNA binding (12,14), which was further molecular evidence for a mechanism through which fusion illustrated by reports that the critical basic region residues of proteins act as modifier oncogenes that subvert differentia- the C/EBPα protein-DNA interaction were identified by an tion in the granulocytic lineage by inhibiting the activity of X-ray structure assay (14). Although there is a predominant C/EBPα. C/EBPα mutation pattern in AML patients, the majority of epigenic modification is envisioned as an important epigen- AML patients always have more than one C/EBPα muta- etic mechanism that regulates the expression of myeloid-specific tion (13,15). In addition, reduced expression could disrupt the genes in the hematopoietic system during leukemogenesis (24). function of C/EBPα for normal hematopoiesis (16). A detailed Hypermethylation of the C/EBPα promoter was first reported study showed that deletion of the C/EBPα gene led to arrest at preferentially in AML-M2 patients (25). The methylation the CMP to GMP transition, thereby causing reduced forma- status of the C/EBPα gene in chronic myeloid leukemia (CML) tion of both granulocytes and monocytes (7). In addition, patients was also investigated, and the data suggested that ONCOLOGY REPORTS 33: 2099-2106, 2015 2101 for tumorigenesis. Notably, during this process, COP1, which contains
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