C/EBPα and C/EBPɛ induce the monocytic differentiation of myelomonocytic cells with the MLL-chimeric fusion gene

Matsushita, Hiromichi; Nakajima, Hitoshi; Nakamura, Yoshihiko; Tsukamoto, Hideo; Tanaka, Yuka; Gui-lan, Jin; Yabe, Miharu; Asai, Satoshi; Ono, Ryoichi; Nosaka, Tetsuya; Sugita, Kanji; Morimoto, Akira; Hayashi, Yasuhide; Hotta, Tomomitsu; Ando, Kiyoshi; Miyachi, Hayato

doi:10.1038/onc.2008.285

Cited by 23 publications

(15 citation statements)

References 40 publications

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“…Taken together with the observation that null mutations of CEBPA are almost never seen in AML, our data suggest that some residual function of CEBPA is required for transformation (29). Although these findings are surprising, given that high levels of CEBPA have been shown to promote myeloid differentiation (22), it is most likely that a moderate level of CEBPA is required for HOXA9-mediated AML.…”

Section: Discussionmentioning

confidence: 45%

“…Whereas Cebpa −/− mice show complete loss of the granulocytic compartment, recent work shows that loss of C/EBPα in adult HSCs leads to both an increase in the number of functional HSCs and an increase in their proliferative and repopulating capacity (19,20). Conversely, CEBPA overexpression can promote transdifferentiation of a variety of fibroblastic cells to the myeloid lineage and can induce monocytic differentiation in MLL-fusion protein-mediated leukemias (21,22).…”

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confidence: 99%

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C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis

Collins

Wang

Miao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Acute myeloid leukemia (AML) is a highly heterogeneous form of cancer that results from the uncontrolled proliferation of primitive immune cells. Homeobox A9 (HOXA9) is an evolutionarily conserved transcription factor that is overexpressed in a large percentage of AML cases and is associated with a poor prognosis. Here, we show that CCAAT/enhancer binding protein alpha (C/EBPα), a transcription factor involved in immune cell development that is commonly mutated in AML, is a critical collaborator required for HOXA9-mediated leukemic transformation. We also establish that the cell cycle regulator cyclin-dependent kinase inhibitors Cdkn2a/b are corepressed by the Hoxa9–C/EBPα complex. These findings suggest a novel functional interaction between two leukemic transcription factors, HOXA9 and C/EBPα, that is altered in a large percentage of AML cases.

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Section: Discussionmentioning

confidence: 45%

mentioning

confidence: 99%

C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis

Collins

Wang

Miao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…These were Hoxb4 that promotes self-renewal by HSC, Cebpa that drives granulocyte lineage commitment, and Cebpe that drives late granulocyte maturation and terminates proliferation. 22, 23, 24, 25, 26, 27 Repression of Hoxb4 and activation of Cebpa by G-CSF was similar in wild-type and Runx1 -haploinsufficient cells (Figure 2a). Despite the upregulation of Cebpa, Cebpe activation was significantly decreased in the Runx1 -haploinsufficient cells, even after 15 days of culture with G-CSF (Figure 2a).…”

Section: Resultsmentioning

confidence: 84%

Runx1 deficiency permits granulocyte lineage commitment but impairs subsequent maturation

Ebrahem

et al. 2013

Oncogenesis

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First-hits in the multi-hit process of leukemogenesis originate in germline or hematopoietic stem cells (HSCs), yet leukemia-initiating cells (LICs) usually have a lineage-committed phenotype. The molecular mechanisms underlying this compartment shift during leukemia evolution have not been a major focus of investigation and remain poorly understood. Here a mechanism underlying this shift was examined in the context of Runx1 deficiency, a frequent leukemia-initiating event. Lineage-negative cells isolated from the bone marrow of Runx1-haploinsufficient and wild-type control mice were cultured in granulocyte-colony-stimulating factor to force lineage commitment. Runx1-haploinsufficient cells demonstrated significantly greater and persistent exponential cell growth than wild-type controls. Not surprisingly, the Runx1-haploinsufficient cells were differentiation-impaired, by morphology and by flow-cytometric evaluation for granulocyte differentiation markers. Interestingly, however, this impaired differentiation was not because of decreased granulocyte lineage commitment, as RNA and protein upregulation of the master granulocyte lineage-commitment transcription factor Cebpa, and Hoxb4 repression, was similar in wild-type and Runx1-haploinsufficient cells. Instead, RNA and protein expression of Cebpe, a key driver of progressive maturation after lineage commitment, were significantly decreased in Runx1-haploinsufficient cells. Primary acute myeloid leukemia cells with normal cytogenetics and RUNX1 mutation also demonstrated this phenotype of very high CEBPA mRNA expression but paradoxically low expression of CEBPE, a CEBPA target gene. Chromatin-immunoprecipitation analyses suggested a molecular mechanism for this phenotype: in wild-type cells, Runx1 binding was substantially greater at the Cebpe than at the Cebpa enhancer. Furthermore, Runx1 deficiency substantially diminished high-level Runx1 binding at the Cebpe enhancer, but lower-level binding at the Cebpa enhancer was relatively preserved. Thus, Runx1-deficiency permits Cebpa upregulation and the exponential cell growth that accompanies lineage commitment, but by impairing activation of Cebpe, a key proliferation-terminating maturation gene, extends this exponential growth. These mechanisms facilitate germline cell or HSC of origin, yet evolution into LIC with lineage-committed phenotype.

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“…In acute promyelocytic leukemia cancer-initiating cells, C/EBPα expression is down-regulated, possibly through a methylation-dependent mechanism, indicating that C/EBPα deregulation may contribute to the transformation of these cells [24]. The ectopic expression of C/EBPα can induce the monocytic differentiation of myelomonocytic leukemic cells through the down-regulation of Myc gene [25]. …”

Section: Discussionmentioning

confidence: 99%

Down-regulation of the expression of CCAAT/enhancer binding protein α gene in cervical squamous cell carcinoma

et al. 2014

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BackgroundCervical carcinoma is the second most common cancer and is an important cause of death in women worldwide. CCAAT/enhancer binding proteins (C/EBPs) are a family of transcription factors that regulate cellular differentiation and proliferation in a variety of tissues. However, the role of C/EBPα gene in cervical cancer is still not clear.MethodsWe investigated the expression of C/EBPα gene in cervical squamous cell carcinoma. C/EBPα mRNA level was measured by real-time quantitative RT-PCR in cervical cancer tissues and their adjacent normal tissues. C/EBPα protein level was measured by immunohistochemistry. Methylation in the promoter of C/EBPα gene was detected by MALDI TOF MassARRAY. We transfected HeLa cells with C/EBPα expression vector. C/EBPα expression in HeLa cells was examined and HeLa cell proliferation was measured by MTT assay and HeLa cells migration was analyzed by matrigel-coated transwell migration assays.ResultsThere were significant difference in C/EBPα protein expression between chronic cervicitis and cervical carcinoma (P < 0.001). CEBPα mRNA level was significantly lower in cervical cancer tissues than in normal cervical tissues (P < 0.01). Methylation of the promoter of CEBPα gene in CpG 5, CpG-14.15, CpG-19.20 were significantly higher in cervical cancer than in normal cervical tissues (P < 0.05, P < 0.01, P < 0.05, respectively). CEBPα pcDNA3.1 construct transfected into HeLa cells inhibited cell proliferation and decreased cell migration.ConclusionsOur results indicate that reduced C/EBPα gene expression may play a role in the development of cervical squamous cell carcinoma.

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C/EBPα and C/EBPɛ induce the monocytic differentiation of myelomonocytic cells with the MLL-chimeric fusion gene

Cited by 23 publications

References 40 publications

C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis

C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis

Runx1 deficiency permits granulocyte lineage commitment but impairs subsequent maturation

Down-regulation of the expression of CCAAT/enhancer binding protein α gene in cervical squamous cell carcinoma

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