Maeda T, Merghoub T, Hobbs RM, Dong L, Maeda M, Zakrzewski J et al.Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF. Science 316:860-866

Columbia University, New York, New York, United States
Science (Impact Factor: 33.61). 06/2007; 316(5826):860-6. DOI: 10.1126/science.1140881
Source: PubMed


Hematopoietic stem cells in the bone marrow give rise to lymphoid progenitors, which subsequently differentiate into B and T lymphocytes. Here we show that the proto-oncogene LRF plays an essential role in the B versus T lymphoid cell-fate decision. We demonstrate that LRF is key for instructing early lymphoid progenitors in mice to develop into B lineage cells by repressing T cell-instructive signals produced by the cell-fate signal protein, Notch. We propose a new model for lymphoid lineage commitment, in which LRF acts as a master regulator of the cell's determination of B versus T lineage.

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    • "Pokemon, an erythroid myeloid ontogenic factor, is a member of the POK (POZ and Krüppel) family of transcriptional repressors [1]. Pokemon is a master regulator of B-cell and T-cell lymphoid fate and erythroid development and maturation [2,3]. However, aberrant over-expression of Pokemon in some human tumors, such as breast and liver cancer, lymphomas and adult malignant glioma [4–6], plays a key role in oncogenic transformation and tumorigenesis. "
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    ABSTRACT: Pokemon is an important proto-oncogene that plays a critical role in cellular oncogenic transformation and tumorigenesis. Anoikis, which is regulated by Bim-mediated apoptosis, is critical to cancer cell invasion and metastasis. We investigated the role of Pokemon in anoikis, and our results show that Pokemon renders liver cells resistant to anoikis via suppression of Bim transcription. We knocked-down Pokemon in human hepatoma cells QGY7703 with small interfering RNAs (siRNA). Knockdown of Pokemon alone did not significantly affect the growth and survival of QGY7703 cells but notably enhanced their sensitivity to apoptotic stress due to the presence of chemical agents or cell detachment, thereby inducing anoikis, as evidenced by flow cytometry and caspase-3 activity assays. In contrast, ectopic expression of Pokemon in HL7702 cells led to resistance to anoikis. Dual-luciferase reporter and ChIP assays illustrated that Pokemon suppressed Bim transcription via direct binding to its promoter. Our results suggest that Pokemon prevents anoikis through the suppression of Bim expression, which facilitates tumor cell invasion and metastasis. This Pokemon-Bim pathway may be an effective target for therapeutic intervention for cancer.
    International Journal of Molecular Sciences 12/2012; 13(5):5818-31. DOI:10.3390/ijms13055818 · 2.86 Impact Factor
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    • "For example, Bcl6 has been shown to be necessary for both the B cell germinal center reaction [2], [3] as well as for the development of follicular helper T cells [4], [5]. ThPok has been shown to be necessary and sufficient for CD4 T cell development [6] and the B cell versus T cell commitment step is controlled by LRF (leukemia/lymphoma related factor) [7]. Mazr influences CD8 T cell development, in part by regulating the expression of ThPok [8]. "
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    ABSTRACT: In mice, the transcription factor, PLZF, controls the development of effector functions in invariant NKT cells and a subset of NKT cell-like, γδ T cells. Here, we show that in human lymphocytes, in addition to invariant NKT cells, PLZF was also expressed in a large percentage of CD8+ and CD4+ T cells. Furthermore, PLZF was also found to be expressed in all γδ T cells and in all NK cells. Importantly, we show that in a donor lacking functional PLZF, all of these various lymphocyte populations were altered. Therefore, in contrast to mice, PLZF appears to control the development and/or function of a wide variety of human lymphocytes that represent more than 10% of the total PBMCs. Interestingly, the PLZF-expressing CD8+ T cell population was found to be expanded in the peripheral blood of patients with metastatic melanoma but was greatly diminished in patients with autoimmune disease.
    PLoS ONE 09/2011; 6(9):e24441. DOI:10.1371/journal.pone.0024441 · 3.23 Impact Factor
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    • "These proteins have been demonstrated to participate in a wide variety of cellular functions including transcriptional regulation, cellular proliferation, apoptosis, cell morphogenesis, ion channel assembly, and protein degradation through ubiquitination-proteasome system [3-5]. A subset of BTB/POZ proteins have been implicated in human cancer, and they include BCL-6 (B-cell lymphoma 6) [6-9], PLZF (promyelocytic leukemia zinc finger) [10-14], leukemia/lymphoma-related factor (LRF)/Pokemon [15-18], HIC-1 (hypermethylated in cancer-1) [19-23], NAC-1[24-29] and Kaiso [30-33]. "
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    ABSTRACT: Our previous studies showed that ZBTB20, a new BTB/POZ-domain gene, could negatively regulate α feto-protein and other liver-specific genes, concerning such as bio-transformation, glucose metabolism and the regulation of the somatotropic hormonal axis. The aim of this study is to determine the potential clinical implications of ZBTB20 in hepatocellular carcinoma (HCC). Quantitative real-time RT-PCR and Western blot analyses were used to detect expression levels of ZBTB20 in 50 paired HCC tumorous and nontumorous tissues and in 20 normal liver tissues. Moreover, expression of ZBTB20 was assessed by immunohistochemistry of paired tumor and peritumoral liver tissue from 102 patients who had undergone hepatectomy for histologically proven HCC. And its relationship with clinicopathological parameters and prognosis was investigated. Both messenger RNA and protein expression levels of ZBTB20 were elevated significantly in HCC tissues compared with the paired non-tumor tissues and normal liver tissues. Overexpressed ZBTB20 protein in HCC was significantly associated with vein invasion (P=0.016). Importantly, the recurrence or metastasis rates of HCCs with higher ZBTB20 expression were markedly greater than those of HCCs with lower expression (P=0.003, P=0.00015, respectively). Univariate and multivariate analyses revealed that ZBTB20 overexpression was an independent prognostic factor for HCC. The disease-free survival period and over-all survival period in patients with overexpressed ZBTB20 in HCC was significantly reduced. The expression of ZBTB20 is increased in HCC and associated with poor prognosis in patients with HCC, implicating ZBTB20 as a candidate prognostic marker in HCC.
    BMC Cancer 06/2011; 11(1):271. DOI:10.1186/1471-2407-11-271 · 3.36 Impact Factor
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