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Joseph, Meera, Faiza Rab, Karen Panabaker, and Jeff Nisker. "ATL." International Journal of Gynecologic Cancer 25, no. 4 (May 2015): 584–92. http://dx.doi.org/10.1097/igc.0000000000000403.
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ObjectiveFamily physicians in Canada as reported in several studies do not recognize the importance of family history in relation to breast/ovarian cancer and thus Canadian women with strong family histories continue to develop early-onset breast cancer without the knowledge of or ability to make choices regarding increased surveillance or preventative strategies. This study explored the feelings of women who learned about their hereditary risk only after their diagnosis younger than 52 years and who eventually tested positive for a BRCA gene mutation.MethodsThirty-four such women were mailed an invitation to participate in this research including a letter of information, consent form, and discussion prompts for their written narrative response. Rigorous mixed method analyses were performed using Charmaz-based qualitative analyses as well as quantitative analyses.ResultsThirteen women (38.2%) responded with narratives for qualitative analysis from which 4 themes were coconstructed as follows: I, types of emotions; II, emotional response; III, coping with emotions; and IV, advice to women at similar risk. Women felt they should have learned about their hereditary risk from their family physician and through public education before their diagnosis. Although not experienced at the time of diagnosis, anger, frustration, and regret were experienced after receiving their BRCA results. These emotions arose from our research participants’ lack of opportunity for prior genetic counseling and testing opportunity for genetic counseling and testing.ConclusionsWith increased public and physician education, it is hoped that women with significant family histories of breast/ovarian cancer will be identified before diagnosis and given options regarding cancer surveillance and risk reduction strategies.
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Furukawa, Yoshitaka, Ryuji Kubota, Mitsutoshi Tara, Shuji Izumo, and Mitsuhiro Osame. "Existence of escape mutant in HTLV-I tax during the development of adult T-cell leukemia." Blood 97, no. 4 (February 15, 2001): 987–93. http://dx.doi.org/10.1182/blood.v97.4.987.
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Abstract Although Tax protein is the main target of cytotoxic T lymphocyte (CTL) on human T-cell lymphotropic virus type I (HTLV-I)–infected cells, and Tax peptide 11 through 19 binding to HLA-A*02 has been shown to elicit a strong CTL response, there are patients with adult T-cell leukemia (ATL) bearing HLA-A*02. To explore whether there is genetic variation in HTLV-I tax that can escape CTL recognition during the development of ATL, the HTLV-I tax gene was sequenced in 55 patients with ATL, 61 patients with HTLV-I–associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 62 healthy carriers, and it was correlated with the presence of HLA-A*02. First, a premature stop codon in the 5′ half of the tax gene that looses transactivation activity on the viral enhancer was observed in 3 patients with acute and 1 patient with chronic ATL. This stop codon was revealed to emerge after the viral transmission to the patient from sequence analysis in family members with ATL. Second, amino acid change in Tax peptide 11-19 was observed in 3 patients with ATL. CTL assays demonstrated that this altered Tax 11-19 peptide, observed in ATL patients with HLA-A*02, was not recognized by Tax 11-19–specific CTL. Two patients with ATL had large deletions in tax by sequencing, and 5 patients with ATL had deletions in HTLV-I by Southern blotting. These findings suggest that at some stage of ATL development, HTLV-I–infected cells that can escape the host immune system are selected and have a chance to accumulate genetic alterations for further malignant transformation, leading to acute ATL.
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Yamagata, T., J. Nishida, R. Sakai, T. Tanaka, H. Honda, N. Hirano, H. Mano, Y. Yazaki, and H. Hirai. "Of the GATA-binding proteins, only GATA-4 selectively regulates the human interleukin-5 gene promoter in interleukin-5-producing cells which express multiple GATA-binding proteins." Molecular and Cellular Biology 15, no. 7 (July 1995): 3830–39. http://dx.doi.org/10.1128/mcb.15.7.3830.
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Interleukin-5 (IL-5) is produced by T lymphocytes and known to support B-cell growth and eosinophilic differentiation of the progenitor cells. Using ATL-16T cells which express IL-5 mRNA, we have identified a region within the human IL-5 gene promoter that regulates IL-5 gene transcription. This cis-acting sequence contains the core binding motif, (A/T)GATA(A/G), for GATA-binding family proteins and thus suggests the involvement of this family members. In this report, we describe the cloning of human GATA-4 (hGATA-4) and show that hGATA-4 selectively interacts with the -70 GATA site within the IL-5 proximal promoter region. By promoter deletion and mutation analyses, we established this region as a positive regulatory element. Cotransfection experiments revealed that both hGATA-4 and phorbol-12-myristate-13-acetate (PMA)-A23187 stimulation are necessary for IL-5 promoter activation. The requirement for another regulatory element called CLE0, which lies downstream of the -70 GATA site, was also demonstrated. ATL-16T cells express mRNAs of three GATA-binding proteins, hGATA-2, hGATA-3, and hGATA-4, and each of them has a potential to bind to the consensus (A/T)GATA(G/A) motif. However, using ATL-16T nuclear extract, we demonstrated that GATA-4 is the only GATA-binding protein that forms a specific DNA-protein complex with the -70 GATA site. An electrophoretic mobility shift assay with extracts of COS cells expressing GATA-binding proteins showed that GATA-4 has the highest binding affinity for the -70 GATA site among the three GATA-binding proteins. When the transactivation abilities were compared among the three, GATA-4 showed the highest activity. These results demonstrate the selective role of GATA-4 in the transcriptional regulation of the IL-5 gene in a circumstance where multiple members of the GATA-binding proteins are expressed.
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Tatewaki, M., K. Yamaguchi, M. Matsuoka, T. Ishii, M. Miyasaka, S. Mori, K. Takatsuki, and T. Watanabe. "Constitutive overexpression of the L-selectin gene in fresh leukemic cells of adult T-cell leukemia that can be transactivated by human T- cell lymphotropic virus type 1 Tax." Blood 86, no. 8 (October 15, 1995): 3109–17. http://dx.doi.org/10.1182/blood.v86.8.3109.3109.
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Abstract L-selectin is an adhesion molecule of the selectin family that mediates the initial step of leukocyte adhesion to vascular endothelium. Upon cellular activation, expression of the L-selectin gene is downregulated at both the protein and mRNA levels. To understand the mechanism of leukemic cell infiltration into organs, we studied the expression and regulation of L-selectin mRNA in fresh leukemic cells of adult T-cell leukemia (ATL) patients and investigated the response of the L-selectin promoter to human T-cell lymphotropic virus type 1 (HTLV-1) Tax, which is a viral transcriptional transactivator. Flow cytometry showed that L-selectin was expressed on fresh ATL cells along with other activation antigens. Northern blot analysis showed that ATL cells overexpressed that L-selectin mRNA and that the level was aberrantly upregulated after PMA stimulation. Studies using in situ hybridization showed expression of the L-selectin mRNA in the infiltrating leukemic cells in the liver of two ATL patients. Intravenous injection of a rat T-cell line that overexpresses L-selectin showed increased organ infiltration. The induction of Tax expression in JPX9 cells resulted in about a twofold increase in the mRNA expression levels compared with the basal level. Chloramphenicol acetyltransferase (CAT) assay after transient cotransfection showed about a fivefold transactivation of the L-selectin promoter by Tax. The serum level of the shed form of L-selectin was significantly increased in ATL patients (mean +/- SD, 4,215.4 +/- 4,111 ng/mL) compared with those of asymptomatic carriers and healthy blood donors (mean +/- SD, 1,148.0 +/- 269.0 ng/mL and 991.9 +/- 224 ng/mL, respectively). These results indicated that ATL cells constitutively overexpress the L-selectin gene that can be transactivated by HTLV-1 Tax. The overexpression of L-selectin, as well as of inflammatory cytokines, by ATL cells may provide a basis for ATL cells to attach the vascular endothelium, leading to transmigration and organ infitration.
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Tatewaki, M., K. Yamaguchi, M. Matsuoka, T. Ishii, M. Miyasaka, S. Mori, K. Takatsuki, and T. Watanabe. "Constitutive overexpression of the L-selectin gene in fresh leukemic cells of adult T-cell leukemia that can be transactivated by human T- cell lymphotropic virus type 1 Tax." Blood 86, no. 8 (October 15, 1995): 3109–17. http://dx.doi.org/10.1182/blood.v86.8.3109.bloodjournal8683109.
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L-selectin is an adhesion molecule of the selectin family that mediates the initial step of leukocyte adhesion to vascular endothelium. Upon cellular activation, expression of the L-selectin gene is downregulated at both the protein and mRNA levels. To understand the mechanism of leukemic cell infiltration into organs, we studied the expression and regulation of L-selectin mRNA in fresh leukemic cells of adult T-cell leukemia (ATL) patients and investigated the response of the L-selectin promoter to human T-cell lymphotropic virus type 1 (HTLV-1) Tax, which is a viral transcriptional transactivator. Flow cytometry showed that L-selectin was expressed on fresh ATL cells along with other activation antigens. Northern blot analysis showed that ATL cells overexpressed that L-selectin mRNA and that the level was aberrantly upregulated after PMA stimulation. Studies using in situ hybridization showed expression of the L-selectin mRNA in the infiltrating leukemic cells in the liver of two ATL patients. Intravenous injection of a rat T-cell line that overexpresses L-selectin showed increased organ infiltration. The induction of Tax expression in JPX9 cells resulted in about a twofold increase in the mRNA expression levels compared with the basal level. Chloramphenicol acetyltransferase (CAT) assay after transient cotransfection showed about a fivefold transactivation of the L-selectin promoter by Tax. The serum level of the shed form of L-selectin was significantly increased in ATL patients (mean +/- SD, 4,215.4 +/- 4,111 ng/mL) compared with those of asymptomatic carriers and healthy blood donors (mean +/- SD, 1,148.0 +/- 269.0 ng/mL and 991.9 +/- 224 ng/mL, respectively). These results indicated that ATL cells constitutively overexpress the L-selectin gene that can be transactivated by HTLV-1 Tax. The overexpression of L-selectin, as well as of inflammatory cytokines, by ATL cells may provide a basis for ATL cells to attach the vascular endothelium, leading to transmigration and organ infitration.
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Kozako, Tomohiro, Makoto Yoshimitsu, Yohann White, Akiyoshi Aikawa, Teruhisa Shoji, Shinichiro Honda, Hiroshi Shimeno, Shinji Soeda, and Naomichi Arima. "Overexpression of SIRT1, a Longevity Gene-Encoded Protein, and Induction of Apoptosis by Its Inhibition In Adult T-Cell Leukemia Cells." Blood 116, no. 21 (November 19, 2010): 2768. http://dx.doi.org/10.1182/blood.v116.21.2768.2768.
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Abstract Abstract 2768 Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm developing after a long-term infection with human T-cell leukemia virus (HTLV-1), in which NF-kB is also implicated as an exacerbation factor. Despite recent progress in both chemotherapy and supportive care for hematological malignancies, the prognosis of ATL is still poor; overall survival at 3 years is only 24%. New strategies for the therapy and prophylaxis of ATL (e.g., vaccines and novel molecular target agents) are still required. SIRT1, an NAD+-dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, due to its ability to deacetylate numerous substrates, such as histone and NF-kB. Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV-1-related cell lines (S1T and MT-2). Sirtinol-induced apoptosis was mediated by activation of the caspase family, and inactivation of NF-kB, reducing IkBα phosphorylation. Interestingly, NAD+ augmented sirtinol-induced apoptosis following deacetylation of NF-kB via NAD+-dependent deacetylase. Thus, the SIRT1 inhibitor acted as a tumor suppressor, where NAD+ accelerated the SIRT1 inhibitor-induced apoptosis. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells, and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL. Figure 1. SIRT1 inhibitor reduces viability of leukemic cell lines. Cell lines were incubated at 1×105 cells/mL in the presence of various concentrations of sirtinol for 72 h. Proliferation of cell lines in the absence or presence of the indicated concentrations of sirtinol was assessed by WST-8 assay. Data are means ± S.D. from 3 independent experiments. Figure 1. SIRT1 inhibitor reduces viability of leukemic cell lines. Cell lines were incubated at 1×105 cells/mL in the presence of various concentrations of sirtinol for 72 h. Proliferation of cell lines in the absence or presence of the indicated concentrations of sirtinol was assessed by WST-8 assay. Data are means ± S.D. from 3 independent experiments. Disclosures: No relevant conflicts of interest to declare.
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Morosetti, R., N. Kawamata, AF Gombart, CW Miller, Y. Hatta, T. Hirama, JW Said, M. Tomonaga, and HP Koeffler. "Alterations of the p27KIP1 gene in non-Hodgkin's lymphomas and adult T- cell leukemia/lymphoma." Blood 86, no. 5 (September 1, 1995): 1924–30. http://dx.doi.org/10.1182/blood.v86.5.1924.bloodjournal8651924.
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The protein p27KIP1 belongs to a recently identified family of proteins termed cyclin-dependent kinase inhibitors (CDKIs). These proteins play an important role in regulating cell-cycle progression and loss of their function has been implicated in tumorigenesis. Transforming growth factor beta (TGF-beta) may induce cell growth arrest through p27 activation. TGF-beta often loses its ability to arrest growth of transformed cells; this could potentially occur through a defect in p27. To determine the role of p27 in tumorigenesis, we examined its mutational status in 74 non-Hodgkin's lymphomas (NHLs) (52 of B-cell phenotype, 22 of T-cell phenotype), 5 lymphoma cell lines, and 42 adult T-cell leukemias/lymphomas (ATLs) using polymerase chain reaction- single strand conformational polymorphism (PCR-SSCP) and Southern blot analyses. A nonsense mutation (stop codon) that could result in expression of a truncated nonfunctional p27 protein was detected at codon 76 in one case of acute lymphomatous ATL, but not in matched normal tissues. Previously undescribed polymorphisms were also identified at codon 109 in the lymphomas and at codon 55 in the ATLs. Two homozygous deletions of the p27 gene were detected in one case of B- immunoblastic NHL and in one case of acute ATL by Southern blot hybridization. These results indicate that p27 gene alterations are rare events in NHLs and ATLs, but may play an important role in the pathogenesis of some hematologic malignancies.
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Serrano, Mario, Socorro Parra, Luis D. Alcaraz, and Plinio Guzmán. "The ATL Gene Family from Arabidopsis thaliana and Oryza sativa Comprises a Large Number of Putative Ubiquitin Ligases of the RING-H2 Type." Journal of Molecular Evolution 62, no. 4 (March 22, 2006): 434–45. http://dx.doi.org/10.1007/s00239-005-0038-y.
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Huang, Yan, Peifang Jiang, Jiazheng Li, Yanxin Chen, Zhengjun Wu, Lingyan Wang, Ting Yang, and Jianda Hu. "Single-Cell RNA Sequencing Unveils the Hallmarks of Populations at Different Stages of HTLV-1 Infection." Blood 138, Supplement 1 (November 5, 2021): 3323. http://dx.doi.org/10.1182/blood-2021-152438.
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Abstract Background Adult T-cell leukemia-lymphoma (ATL) is an aggressive mature T-cell neoplasm caused by human T -cell leukemia virus type 1 (HTLV-1). Up to 5% of infected individuals develop to ATL. HTLV-1 preferentially infects CD4 + T cells, and stimulates cell proliferation and prevents cell death by apoptosis. The viral oncogene-encoded proteins, Tax and HBZ, play important roles in viral infection and cell immortalization. However, the host factor of developing from carrier to patient is not clear. Results To characterize the heterogeneity of ATL patients, we performed single-cell RNA-sequencing (10x Genomics) analysis on single cell suspensions isolated from PBMCs of nine samples, including three ATL patients, three HTLV-1 asymptomatic carriers as well as three healthy donors (HD). We acquired 82977 high-quality cells with a median of 1718 genes detected per cell. Unsupervised clustering using Seurat followed by visualization in t-Stochastic Neighbor Embedding (t-SNE) identified 29 distinct cell clusters (Figure 1A). The single cell profiling of ATL patients were significantly different from that of carriers and healthy donors, while the latter two had little difference (Figure 1B). Based on singleR packages and marker genes of each cluster, 4 major cell populations (T cells, NK cells, B cells and myeloid cells) and other rare cell types were annotated, such as erythrocyte cluster and eosinophils cluster. We observed an enrichment of CD4 + T cell from patients in 4 cluster (Figure 1C), which proportion of cells was higher than that of carriers and healthy donors. According to cell type annotation, cells from cluster 11 were CD4 + CD25 + Foxp3 + Treg cells. Based on the increasing proportion of cluster 11 in healthy people, carriers and patients, without significant statistical differences, we assumed that Foxp3 + Treg cells were involved in the evolution of ATL tumor cells. That was identical with published literatures. To investigate the differences between tumor and normal CD4 + T cell, the gene expression was compared among 7 clusters of CD4 + T cell from three groups. Using a threshold of p value < 0.05 and | fold change| >2. Through integrated analysis, we identified 26 commonly upregulated genes (gene expression level: patients > carriers > HD) and 9 downregulated genes (gene expression level: patients < carriers < HD. To further analyze the biological function of the common DEGs, gene ontology (GO) analysis showed that these genes could be mainly categorized into plasma membrane and protein binding. Subsequently, we validated the mRNA expression level of upregulated common DEGs among three groups by qRT-PCR. The isolated CD4 + T cell using CD4 microbeads of a total of 6 patients, 3 carriers and 9 normal specimens were included. The result showed that the mRNA expression levels of gene CADM1 and RGS13 in patients were higher than those in carriers and healthy donors, although there was no statistical difference between patients and carriers, and the expression levels of carriers tended to be higher than those in normal people (Figure 1D and E). Previously, CADM1 has been revealed to be highly expressed in HTLV-1-infected CD4 + T cells. Our study confirmed this result by single-cell profiling. RGS13, a member of the regulators of G protein signaling (RGS) family, participates in cellular communication. The role of RGS13 in ATL needs to be investigated. Conclusions This study is the first time to analyze the single-cell RNA level of ATL patients, HTLV-1 virus carriers and normal people. The peripheral blood cell composition of the patient is significantly different from that of the carriers and healthy donors, while it is similar between carriers and normal people. CD4 + T cells are the main cell population of patients. The proportion of CD4 + CD25 + Foxp3 + Treg cells increased gradually in healthy people, carriers and patients. DEGs analysis showed that CADM1 and RGS13 were highly expressed in CD4 + T cells of patients, followed by carriers, validated by 18 clinical samples. However, the molecular mechanism of RGS13 in the process from HTLV-1 infection to ATL needs to be further studied. Figure 1 Figure 1. Disclosures Hu: Astellas Pharma, Inc.: Research Funding.
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Kurita, Daisuke, Jun-ichirou Yasunaga, Azusa Tanaka, Mahgoub Mohamed, and Masao Matsuoka. "Dynamic Changes of Chromatin Structure and Transcriptome By Transient Expression of HTLV-1 Tax in ATL Cells." Blood 132, Supplement 1 (November 29, 2018): 4094. http://dx.doi.org/10.1182/blood-2018-99-111125.
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Abstract Adult T-cell leukemia-lymphoma (ATL) is a fatal malignancy of CD4+ T cells, which is caused by human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 encodes two oncogenic viral factors, Tax and HTLV-1 bZIP factor (HBZ) in the sense and antisense of the provirus respectively. HBZ is constitutively expressed in infected cells and plays critical roles for cell proliferation. Tax potently promotes viral replication and activates various oncogenic signaling pathways in HTLV-1 infected cells; however, Tax expression is generally suppressed in infected cells owing to its high immunogenicity. Therefore, the dynamics of Tax expression and contribution of oncogenic transformation by Tax in HTLV-1 infected cells have not been well elucidated. Recently, we have reported that Tax is transiently expressed in a small subpopulation of ATL cells, which induces drastic changes in the host transcriptional profile (Mahgoub M., et al. Proc Natl Acad Sci USA. 2018). Moreover, the single cell analysis showed that expression of anti-apoptotic and NF-kB related genes were upregulated in Tax-expressing cells compared to Tax-non-expressing cells. HBZ expression was increased in Tax-non-expressing cells than Tax-expressing cells, suggesting that HBZ may regulate cell proliferation in a different time phase from Tax. On the other hand, precise mechanisms for regulation of host gene expression by transient Tax expression are not well known. In this study, we analyzed structural change of host chromatin accompanied by transient Tax expression to clarify the transcriptional dynamics of host genes in ATL cells. ATL cell lines (MT-1 and KK-1), which express EGFP under the control of Tax, were used to sort Tax-expressing and -non-expressing cells by a cell sorter, and each population was subjected to H3K27ac ChIP-seq and ATAC-seq analyses. DNA libraries were quantified and sequenced on Illumina NextSeq 500 (single-end) for ChIP-seq, and on Illumina Hiseq 4000 (paired-end) for ATAC-seq, respectively. H3K27ac ChIP-seq data showed that the peaks correlated with Tax expression were observed in many genetic loci including NF-kB related genes. Among Tax-expressing MT-1 cells, H3K27ac were highly enriched super-enhancers, such as IL2RA, TRAF3, TNFRSF8, PHF13 loci, compared to Tax-non-expressing cells. There were more H3K27ac-marked active enhancers in Tax-expressing cells than Tax-non-expressing cells across the entire region, suggesting that global structural change may occur in Tax-expressing cells. Using the data of ATAC-seq, pathway analyses were performed by GREAT. This analysis revealed that the pathways associated with immune activation, such as Toll-like receptor signaling, TNFR2 signaling, IL-2 signaling, and Th1/Th2 differentiation pathways were significantly enriched in Tax-expressing cells. Analysis of genome-wide distribution of motifs in open chromatin region, were carried out with HOMER, and result showed that motifs of NF-kB, and AP-1 family (e.g., JunB, Fra1, Fra2) were significantly enriched in Tax-expressing cells compared to Tax-non-expressing cells, which is consistent with the results of pathway analyses of RNA-seq. The genome-wide motif footprinting analysis was performed using Protein interaction quantitation (PIQ) methods. It was found that motifs of NF-kB, and AP-1 family (e.g., JunB, Fra1, Fra2) were occupied in large number of regions and showed higher DNA accessibility in Tax-expressing cells. In contrast, motif of CTCF was likely occupied in large number of regions and exhibit higher DNA accessibility in Tax-non-expressing cells. Importantly, mRNA levels of NF-kB and AP-1 transcription factors were significantly higher in Tax-expressing than Tax-non-expressing cells. These findings suggest that structural changes of NF-kB and AP-1 family recognition sites, and activation of pathways related to these factors could trigger global transcriptional changes in host genome by transient Tax expression, which is the critical event for persistent infection of HTLV-1 and leukemogenesis of ATL. Disclosures Matsuoka: Bristol Myers Squibb: Research Funding.
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Kataoka, Keisuke, Yasunobu Nagata, Akira Kitanaka, Yuichi Shiraishi, Jun-ichirou Yasunaga, Yasushi Totoki, Kenichi Chiba, et al. "Frequent Activating Somatic Alterations in T-Cell Receptor / NF-κb Signaling in Adult T-Cell Leukemia/Lymphoma." Blood 126, no. 23 (December 3, 2015): 113. http://dx.doi.org/10.1182/blood.v126.23.113.113.
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Abstract Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm of largely unknown genetic basis, which is associated with human T-cell leukemia virus type-1 (HTLV-1) infection. To delineate a genetic landscape of somatic alterations in ATL, we have performed an integrated genetic study, in which whole-genome/exome (WGS/WES) and transcriptome sequencing (RNA-seq) was performed for a cohort of 83 paired ATL samples, followed by extensive validation using targeted sequencing of detected mutations in 370 follow-up samples. A striking feature of driver lesions in ATL was their strong enrichment in the components of T-cell receptor (TCR) / NF-κB pathway. Accounting for more than 90% of ATL cases, these lesions were characterized by the predominance of activating alterations, including hotspot missense mutations in PLCG1 (36%), PRKCB (33%), CARD11 (24%), VAV1 (18%), IRF4 (14%) and FYN (4%). Among these, most frequently mutated was PLCG1, which encodes phospholipase C γ1 (PLCγ1), a key regulator of the proximal TCR signaling. Besides the S345F and S520F mutations recently reported in cutaneous T-cell lymphoma, we identified an additional hotspot mutations (R48W, E1163K, and D1165H). The second most frequently mutated gene was PRKCB, encoding a member of the protein kinase C (PKC) family of proteins (PKCβ), a pivotal signaling molecule downstream of PLCγ. The frequent mutations of PKCβ were unexpected, because it is PKCθ that has been implicated in TCR signaling, whereas PKCβ has been more focused in the context of B-cell receptor signaling. Approximately 93% of the PRKCB mutations were confined to the catalytic domain with a prominent hotspot at D427, suggesting gain-of-function nature of these mutations. Consistent with this, when transduced with the D427N PKCβ mutant, HEK293T and/or Jurkat cells showed increased membrane translocation after PMA/Ionomycin-stimulation, enhanced IKK phosphorylation and p65 nuclear translocation, and augmented NF-κB transcription, compared to wild-type PKCβ-transduced cells. Thus, these PRKCB mutations are the first activating mutations of this family identified in human cancers. Downstream to PKC lies CARD11, a scaffolding protein required for antigen receptor-induced NF-κB activation. Although previously reported in B-cell lymphomas, CARD11 mutations were more common in ATL (24%). In B-cell lymphomas, mutations are largely limited to the coiled-coil (CC) domain, whereas in ATL, they were clustered not only within the CC domain, but also within the PKC-responsive inhibitory domain, showing a prominent mutational hotspot at E626. The inhibitory domain has been implicated in autoinhibition, whose deletion leads to constitutive activation of CARD11. Intriguingly, WGS identified small intragenic deletions confined to this domain (exons 14-17) in 4 cases (8%) without canonical mutations, and RNA-seq confirmed the skipping of the corresponding exons in these cases. Remarkably, CARD11 mutation significantly co-occurred with PRKCBmutations, suggesting potential functional synergism between these lesions. Actually, overexpression of wild-type CARD11 induced NF-κB activation, which was further augmented by E626K mutation. Similarly, when both CARD11 (E626K) and PRKCB (D427N) mutants were co-expressed, more enhanced NF-κB activation was observed. RNA-seq and follow-up RT-PCR screening also identified novel gene fusions in TCR / NF-κB pathway: five CTLA4-CD28 and three ICOS-CD28 fusions were observed in seven (7%) of the 105 cases examined, of whom one patient carried both chimeric fusions. WGS revealed tandem duplications of 2q33.2 segments containing CD28, CTLA4, and ICOS, compatible with the corresponding fusion transcripts. B7/CD28 co-signaling molecules, including CD28, CTLA4, and ICOS co-receptors, play pivotal roles in positive and negative regulations of TCR signaling. All the predicted chimeric proteins had the cytoplasmic part of CD28, and are expected to be expressed under the control of the regulatory element of CTLA4 or ICOS, likely leading to prolonged expression of CD28 co-stimulator. Our findings suggest that deregulated TCR / NF-κB pathway caused by genetic alterations is a hallmark of ATL pathogenesis. The predominance of gain-of-function mutations in this pathway offers good opportunities for exploiting these mutations for the targets of novel drugs to better manage patients. Disclosures Tobinai: Gilead Sciences: Research Funding. Miyazaki:Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Chugai: Honoraria, Research Funding; Shin-bio: Honoraria; Kyowa-Kirin: Honoraria, Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.
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Takai, Ryota, Koji Hasegawa, Hanae Kaku, Naoto Shibuya, and Eiichi Minami. "Isolation and analysis of expression mechanisms of a rice gene, EL5, which shows structural similarity to ATL family from Arabidopsis, in response to N-acetylchitooligosaccharide elicitor." Plant Science 160, no. 4 (March 2001): 577–83. http://dx.doi.org/10.1016/s0168-9452(00)00390-3.
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Arnold, Joshua, Bevin Zimmerman, Min Li, Michael D. Lairmore, and Patrick L. Green. "Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation." Blood 112, no. 9 (November 1, 2008): 3788–97. http://dx.doi.org/10.1182/blood-2008-04-154286.
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Human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) is dispensable for HTLV-1–mediated cellular transformation in cell culture, but is required for efficient viral infectivity and persistence in rabbits. In most adult T-cell leukemia (ATL) cells, Tax oncoprotein expression is typically low or undetectable, whereas Hbz gene expression is maintained, suggesting that Hbz expression may support infected cell survival and, ultimately, leukemogenesis. Emerging data indicate that HBZ protein can interact with cAMP response element binding protein (CREB) and Jun family members, altering transcription factor binding and transactivation of both viral and cellular promoters. Herein, lentiviral vectors that express Hbz-specific short hairpin (sh)–RNA effectively decreased both Hbz mRNA and HBZ protein expression in transduced HTLV-1–transformed SLB-1 T cells. Hbz knockdown correlated with a significant decrease in T-cell proliferation in culture. Both SLB-1 and SLB-1-Hbz knockdown cells engrafted into inoculated NOD/SCIDγchain−/− mice to form solid tumors that also infiltrated multiple tissues. However, tumor formation and organ infiltration were significantly decreased in animals challenged with SLB-1-Hbz knockdown cells. Our data indicate that Hbz expression enhances the proliferative capacity of HTLV-1–infected T cells, playing a critical role in cell survival and ultimately HTLV-1 tumorigenesis in the infected host.
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Twizere, Jean-Claude, Jean-Yves Springael, Mathieu Boxus, Arsène Burny, Franck Dequiedt, Jean-François Dewulf, Julie Duchateau, et al. "Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling." Blood 109, no. 3 (September 21, 2006): 1051–60. http://dx.doi.org/10.1182/blood-2006-06-026781.
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AbstractHuman T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene expression leading to T-cell transformation. Guanine nucleotide–binding proteins (G proteins) and G protein–coupled receptors (GPCRs) constitute the largest family of membrane proteins known and are involved in the regulation of most biological functions. Here, we report an interaction between HTLV-1 Tax oncoprotein and the G-protein β subunit. Interestingly, though the G-protein β subunit inhibits Tax-mediated viral transcription, Tax-1 perturbs G-protein β subcellular localization. Functional evidence for these observations was obtained using conditional Tax-1–expressing transformed T-lymphocytes, where Tax expression correlated with activation of the SDF-1/CXCR4 axis. Our data indicated that HTLV-1 developed a strategy based on the activation of the SDF-1/CXCR4 axis in the infected cell; this could have tremendous implications for new therapeutic strategies.
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Gitlin, Scott D., and Matthew D. Morse. "Functional Interactions of Ets1 with Viral and Cellular Proteins Mediate Ets1’s Effects on Transcription and the Pathogenesis of Adult T-Cell Leukemia/Lymphoma." Blood 106, no. 11 (November 16, 2005): 2608. http://dx.doi.org/10.1182/blood.v106.11.2608.2608.
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Abstract Members of the ets gene family have been implicated in the pathogenesis of a variety of hematologic malignancies. The Ets1 proto-oncogene is a DNA-binding, sequence-specific transcriptional activator of several cellular and viral gene promoters, including the long terminal repeat (LTR) of the human T-lymphotropic virus type I (HTLV-I). Ets1 has the ability to transform both erythroid and myeloid progenitor cells and has been implicated in the formation of certain leukemias. In our studies to understand adult T-cell leukemia/lymphoma (ATL), we have previously shown that Ets1 cooperatively interacts with HTLV-I Tax1 to synergistically transactivate the HTLV-I LTR and cellular promoters. We hypothesize that Ets1’s transcriptional effects on viral and cellular gene expression contributes to the development and manifestations of ATL. The interaction between Ets1 and Tax1 raises the possibility that Ets1 plays a role in the transformation of HTLV-I-infected T-lymphocytes and in the clinical manifestations of ATL. However, little is known about how Ets1 regulates gene expression and participates in transformation events. Electrophoretic mobility shift assays demonstrate that although Ets1 can bind to specific DNA elements, binding to the HTLV-I LTR and other promoters is not necessary for Ets1’s transcriptional activity when Tax1 is present. Deletion mutagenesis of Ets1 identifies that the amino terminal, central and distal carboxy terminal domains of Ets1 individually increase transcription from the HTLV-I LTR. The DNA-recognition domain-containing proximal carboxy terminal region of Ets1 inhibits HTLV-I LTR transcription. Only wild type Ets1 and a protein consisting of the entire carboxy terminus bind to the HTLV-I LTR. Transcriptional activity of truncated Ets1 proteins is not dependent on their LTR-binding ability. The synergistic Ets1/Tax1 interaction appears to require the involvement of additional cellular proteins, including the cAMP response element binding protein (CREB). In transient transfections of CREB-deficient cells, functional CREB cooperatively interacts with Ets1 to transactivate the HTLV-I LTR. In the presence of CREB, Tax1 has an additive effect on Ets1 transactivation. CREB appears to interact with specific Ets1 domains in mediating transcriptional activity and may involve an NF-kB pathway. SP1 transactivation of the HTLV-I LTR is independent of Ets1 or Tax1. Transient transfection of SP1-deficient cells reveals that SP1 transactivation of the HTLV-I LTR is independent of Ets1 or Tax1. Ets1 has no transcriptional activity on the HTLV-I LTR in the absence of SP1. These results demonstrate that: (1) Ets1 contains multiple functional domains that likely interact in mediating transcription from the HTLV-I LTR and which are not dependent on DNA binding; (2) Ets1 requires the presence of specific cellular and/or viral proteins to mediate its activities; and (3) HTLV-I Tax1, CREB, possibly NF-kB, and perhaps other cellular proteins mediate Ets1’s transcriptional activity. Further elucidation of Ets1 interactions with cellular and viral proteins is important for understanding Ets1’s role in cellular and disease processes.
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Takaku, Tomoiku, Junko H. Ohyashiki, Yu Zhang, and Kazuma Ohyashiki. "Estimating Immunoregulatory Gene Networks in Human Herpesvirus Type 6 (HHV-6)-Infected T Cells." Blood 106, no. 11 (November 16, 2005): 2381. http://dx.doi.org/10.1182/blood.v106.11.2381.2381.
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Abstract The immune response to viral infection involves complex network of dynamic gene and protein interactions. Comprehensive gene expression analysis of the host immune response against viruses has been extensively studied, however, the mechanism of virus-induced immune response is not completely understood. This might be due in part to the difficulty of finding pathologically relevant genes, despite the fact that DNA microarray technology can simultaneously monitor the expression of thousands of genes. Likewise, it is hard to estimate how each gene interferes during the viral infection. Thus, construction of gene networks from microarray gene expression data is becoming an important challenge in the post-genome era. Human herpesvirus 6 (HHV-6) is a β-herpesvirus that is closely related to human cytomegalovirus. HHV-6 shows a predominant tropism for CD4 T lymphocytes, on which it exerts marked cytopathic effects. Understanding of the clinical spectrum of HHV-6 is still evolving, however, in vitro interactions between HHV-6 and other viruses, such as the human immunodeficiency virus (HIV), and their relevance to the in vivo situation has become increasingly apparent. We present here the dynamic gene network of the host immune response during human herpesvirus type 6 (HHV-6) infection in an adult T cell leukemia (ATL) cell line. Using a pathway-focused oligonucleotide DNA microarray, we found a possible association between chemokine genes regulating Th1/Th2 balance and genes regulating T-cell proliferation during HHV-6B infection. Gene network analysis using an integrated comprehensive workbench, VoyaGene® revealed that a gene encoding a TEC-family kinase, ITK, might be a putative modulator in the host immune response against HHV-6B infection. We conclude that Th2-dominated inflammatory reaction in host cells may play an important role in HHV-6B infected T cells, thereby suggesting the possibility that ITK might be a therapeutic target in diseases related to dysregulation of Th1/Th2 balance. This study describes a novel approach to find genes related with the complex host-virus interaction using microarray data employing the Bayesian statistical framework. Figure Figure
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Yamagata, T., K. Mitani, H. Ueno, Y. Kanda, Y. Yazaki, and H. Hirai. "Triple synergism of human T-lymphotropic virus type 1-encoded tax, GATA-binding protein, and AP-1 is required for constitutive expression of the interleukin-5 gene in adult T-cell leukemia cells." Molecular and Cellular Biology 17, no. 8 (August 1997): 4272–81. http://dx.doi.org/10.1128/mcb.17.8.4272.
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Accumulated evidence demonstrates that adult T-cell leukemia (ATL) is frequently associated with eosinophilia, and human T-lymphotropic virus type 1 (HTLV-1)-infected cells frequently express interleukin-5 (IL-5). However, the molecular mechanism of constitutive IL-5 expression in HTLV-1-infected cells remains unclear. To clarify the mechanism of aberrant IL-5 expression in HTLV-1-infected cells, we investigated the response of the human IL-5 promoter to the HTLV-1-encoded protein Tax. Cotransfection experiments using Jurkat cells revealed that Tax is incapable of activating the IL-5 promoter by itself but that it synergistically transactivates the promoter with GATA-binding protein (GATA-4) and 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation. By introducing a series of mutations within the IL-5 promoter, we found that conserved lymphokine element 0 (CLE0) is responsible for mediating the signal induced by Tax-TPA. A deletion construct of the promoter indicated that the -75 GATA element and CLE0 are sufficient to mediate synergistic activation of the IL-5 promoter. Electrophoretic mobility shift assays using Jurkat cell nuclear extracts demonstrated that TPA induces a transcription factor to bind CLE0, and an experiment using JPX-9 cell nuclear extracts showed that Tax enhances this binding activity. An antibody supershift experiment revealed that this band consists of c-Jun and JunD. However, among the Jun family members, only c-Jun is able to cooperate with Tax and GATA-4 to activate the IL-5 promoter. We have determined the minimum factors required for IL-5 gene activation by reconstituting the IL-5 promoter activity in F9 cells. This is the first report to demonstrate the functional involvement of Tax protein in IL-5 gene regulation and to suggest the functional triple synergism among Tax, GATA-4, and AP-1, which disrupts regulated control of the gene and leads to constitutive expression of the IL-5 gene.
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Kawahara, Masahiro, Toshiyuki Hori, Kazuhisa Chonabayashi, Tsutomu Oka, Marius Sudol, and Takashi Uchiyama. "Kpm/Lats2 of the Hippo Pathway Is Linked to Chemo-Sensitivity of Leukemic Cells." Blood 112, no. 11 (November 16, 2008): 1797. http://dx.doi.org/10.1182/blood.v112.11.1797.1797.
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Abstract The Hippo pathway is now recognized as a major signaling network for development and organ size control in mammals as well as in Drosophila melanogaster. We previously identified human kpm/Lats2, the key serine/threonine kinase in the Hippo pathway, and reported that its overexpression induced cell cycle arrest and apoptosis. Down-regulation of kpm/Lats2 expression has been described in various malignancies. It is of particular importance in hematology that low expression of kpm/Lats2 has been reported to be associated with poor prognosis in acute lymphoblastic leukemia. In the present study, we first measured the expression level of kpm/Lats2 mRNA in various hematological malignancies and found that it was markedly decreased in adult T cell leukemia (ATL) and NK cell leukemia/lymphoma, both of which are known to be highly resistant to conventional chemotherapy. In order to investigate the relationship between down-regulation of kpm/Lats2 expression and chemo-resistance, we made kpm/Lats2-knockdown sublines from KG-1a, an AML-derived cell line, and ED-40515+, an ATL-derived cell line, by using shRNA-expression retrovirus vector targeting kpm/Lats2. Silencing of kpm/Lats2 expression in both leukemic cell lines did not change the rate of cell growth but rendered them resistant to DNA damage-inducing agents such as DOX and ETP. Expression of p21 and PUMA was strongly induced by these agents in control cells, despite defective p53, but was only slightly induced in kpm/Lats2-knockdown cells. DNA damage-induced nuclear accumulation of p73, a member of p53 family, was clearly observed in control cells but hardly detected in kpm/Lats2-knockdown cells. ChIP assay showed that p73 was recruited to the puma gene promoter in control cells but not in kpm/Lats2-knockdown cells after DNA damage stress. The analyses with transient co-expression of Kpm/Lats2, YAP2, and p73 showed that Kpm/Lats2 contributed to the stability of YAP2 and p73, which was dependent on the kinase function of Kpm/Lats2 and YAP2 phosphorylation at serine 127. These results strongly suggest that Kpm/Lats2 is involved in the fate of p73 and the induction of p73-target genes that underlie chemo-sensitivity of leukemic cells.
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DeLisi, Matt, Kevin M. Beaver, Michael G. Vaughn, and John Paul Wright. "All in the Family." Criminal Justice and Behavior 36, no. 11 (October 19, 2009): 1187–97. http://dx.doi.org/10.1177/0093854809342884.
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A range of Gene × Environment interactions is associated with antisocial phenotypes, and the evidence is clear that the etiology of antisocial behavior is strongly heritable and that environmental liabilities are important. However, the precise ways that genetic and environmental pathogens interact to predict antisocial behavior are underspecified. The present study shows that the interaction between a polymorphism in a dopamine receptor gene (DRD2) and a criminal father predicts five antisocial phenotypes among African American females ( n = 232) in the National Longitudinal Study of Adolescent Health. Genetic risk (as measured by the A1 allele) and a criminal father interacted to predict serious and violent delinquency at Wave 1, serious and violent delinquency at Wave 2, and number of police contacts. The current investigation represents the first study to show Gene × Environment interactions in the prediction of antisocial phenotypes using criminal justice system status as an environmental pathogen.
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Tsukada, Junichi, Takehiro Higashi, Atsushi Iwashige, Takefumi Katsuragi, Naho Nomura, Takahiro Yamaguchi, Tsukasa Nakanishi, et al. "Lipopolysaccharide(LPS)-Induction of the HTLV-1 LTR in Monocytes." Blood 118, no. 21 (November 18, 2011): 2167. http://dx.doi.org/10.1182/blood.v118.21.2167.2167.
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Abstract Abstract 2167 The human leukemia virus type 1 (HTLV-1) gene expression is regulated by the viral proteins and various cellular transcription factors. HTLV-1 genome encodes not only structural proteins, but also non-structural proteins such as Tax, a transcriptional activator for STAT5 p12I, and HTLV-1 bZIP factor (HBZ) encoded by the minus strand of the viral genome. The functional analysis of the viral proteins such as Tax has shed light on the pathogenesis of adult T cell leukemia/lymphoma (ATL). Expression of Tax is enhanced by T-cell activation stimuli such as phorbol ester (PMA), phytohemagglutinin (PHA) or sodium butyrate in chronically HTLV-1-infected CD4+T-cells. Transgenic mouse studies with Tax expression under the control of the granzyme B promoter or the proximal Lck promoter showed that disease progression is associated with infiltration of activated T- and inflammatory cells, and dysregulated inflammatory cytokine production. More recently, a transgenic mouse model with Tax expression regulated by the LTR (LTR-Tax) showed that LTR-Tax CD4 positive T-cells are hyper-proliferative and hyper-responsive to immune stimulation and strongly produce Th1-, Th2- and Th17-associated cytokines. In addition, HTLV-1 infection causes inflammatory disease of the central nerve system, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as ATL. Aberrant cytokine gene expression is the hallmark of HTLV-1-associated diseases. HTLV-1 infection is widely distributed among mammalian cells. We previously demonstrated that Tax transactivates the promoter of human proIL-1β gene (IL1B) gene through association with two transcription factors, NF-IL6 (C/EBPβ) and Spi-1 (PU.1) in monocytes. Tax synergized with lipopolysaccharide (LPS) to induce IL1B promoter activity. Spi-1 is an Ets family protein restricted in expression to monocytes/myelocytes, B cells, mast cells and erythrocyte stem cells, while NF-IL6 is widely expressed. LPS, a component of the gram-negative bacterial cell wall involved in the activation of monocytes, binds to TLR4, leading to activation of TRAF6, IRAK and MyD88. We now extend these studies to elucidate roles of LPS and Tax on HTLV-1 LTR promoter regulation in monocytes. When HTLV-1 LTR reporter was transfected into THP-1 monocytic cells, LPS dose-dependently induced HTLV-1 LTR. The mid-LTR of the HTLV-1 gene possesses three potential Ets binding elements centered on a GGAA motif (PuB1, pets and PuB2). Elf-1 has been shown to be the predominant protein binding to the HTLV-1 Ets sites in Jurkat and peripheral blood T-cells. In the present study, mutation of the Ets sites, especially pets and PuB2 caused significant inhibition of LPS-induced LTR activity in THP-1 cells. EMSA studies using THP-1 nuclear extracts showed binding of Spi-1 to the HTLV-1 Ets sites in THP-1 cells. Anti-Spi-1 Ab, but not anti-Elf-1 Ab or anti-ets-1 Ab supershifted the complex generated by THP-1 nuclear extract and HTLV-1 LTR Ets site. However, when migration pattern of the complex was compared with recombinant Spi-1 in vitro translated in a reticulocyte lysate system, the THP-1 complex migrated slower than recombinant Spi-1 protein. In this regard, anti-IRF-8 Ab further recognized the slow complex. Several reports recently showed that IRF-8 functions as a heterodimeric complex with spi-1 for expression of relevant genes. On the other hand, when Tax expression vector was cotransfected into THP-1 cells along with HTLV-1 LTR reporter, Tax synergized with LPS to activate LTR. Spi-1 protein has three independent transcriptional activation domains (TAD); a TBP binding region, a Q domain, and a PEST region. GST pull-down studies using GST-Tax and 35S-labeled recombinant Spi-1 revealed that mutant Spi-1 lacking the TADs still retains the ability to interact with Tax. In contrast to THP-1 cells, Jurkat T-cells showed only a marginal increase in IL1B promoter activity following Tax expression. Mutations of the Spi-1 binding site in the IL1B promoter did not affect Tax-induced activity in Jurkat cells. Any factors did not bind to the IL1B Spi-1 site in Jurkat cells. Thus, our data suggest that LPS cooperates with Tax to activate the viral and various cellular genes in HTLV-1-infected monocytes. Spi-1 is a key player in the monocyte-specific gene regulation in HTLV-1 infection. Disclosures: No relevant conflicts of interest to declare.
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Chen, Chongxiang, Siliang Chen, Ma Luo, Honghong Yan, Lanlan Pang, Chaoyang Zhu, Weiyan Tan, Qingyu Zhao, Jielan Lai, and Huan Li. "The role of the CDCA gene family in ovarian cancer." Annals of Translational Medicine 8, no. 5 (March 2020): 190. http://dx.doi.org/10.21037/atm.2020.01.99.
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Ma, Fang, Yali Zou, Ruilin Ma, Xin Chen, and Lanfang Ma. "Evolution, characterization and expression analysis of Sox gene family in rainbow trout (Oncorhynchus mykiss)." Czech Journal of Animal Science 67, No. 4 (April 30, 2022): 157–66. http://dx.doi.org/10.17221/4/2022-cjas.
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The Sox transcription factor family plays an important role in various biological processes such as animal sex determination and multiple organ development. We used online databases to analyze the gene structure, chemical characteristics, and evolutionary relationship of Sox family genes through bioinformatics, and we studied the expression profiles and regulatory mechanisms of Sox family genes. A total of 29 rainbow trout Sox genes were identified. The phylogenetic analysis found that Sox genes of rainbow trout were clustered in seven subfamilies (B1, B2, C, D, E, F and H), and the gene structure of each subfamily was relatively conserved. Furthermore, Sox1, Sox4, Sox6, Sox8, Sox9, Sox11, Sox17, Sox18, and Sox19 developed into two copies, which might be the result of teleost fish-specific genome replication. Multiple HMG box domain alignments indicated that the motifs for all Sox sequences are conserved. Gene expression studies reveal that Sox expression is tissue-specific and that multiple Sox genes are involved in rainbow trout gonad and central nervous system development. Our study provides valuable information on the evolution of teleosts, and will also help to further research the functional characteristics of Sox genes.
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Kumar, Aseem, Anand Kumar, and Joseph E. Parrillo. "Interleukin-1 gene cluster polymorphisms: All in the family *." Critical Care Medicine 30, no. 5 (May 2002): 1168–69. http://dx.doi.org/10.1097/00003246-200205000-00041.
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Mendoza, Michael, Garni Mandani, and Jamil Momand. "The MDM2 gene family." BioMolecular Concepts 5, no. 1 (March 1, 2014): 9–19. http://dx.doi.org/10.1515/bmc-2013-0027.
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AbstractMDM2 is an oncoprotein that blocks p53 tumor suppressor-mediated transcriptional transactivation, escorts p53 from the cell nucleus to the cytoplasm, and polyubiquitylates p53. Polyubiquitylated p53 is rapidly degraded in the cytoplasm by the 26S proteasome. MDM2 is abnormally upregulated in several types of cancers, especially those of mesenchymal origin. MDM4 is a homolog of MDM2 that also inhibits p53 by blocking p53-mediated transactivation. MDM4 is required for MDM2-mediated polyubiquitylated of p53 and is abnormally upregulated in several cancer types. MDM2 and MDM4 genes have been detected in all vertebrates to date and only a single gene homolog, named MDM, has been detected in some invertebrates. MDM2, MDM4, and MDM have similar gene structures, suggesting that MDM2 and MDM4 arose through a duplication event more than 440 million years ago. All members of this small MDM2 gene family contain a single really interesting new gene (RING) domain (with the possible exception of lancelet MDM) which places them in the RING-domain superfamily. Similar to MDM2, the vast majority of proteins with RING domains are E3 ubiquitin ligases. Other RING domain E3 ubiquitin ligases that target p53 are COP1, Pirh2, and MSL2. In this report, we present evidence that COP1, Pirh2, and MSL2 evolved independently of MDM2 and MDM4. We also show, through structure homology models of invertebrate MDM RING domains, that MDM2 is more evolutionarily conserved than MDM4.
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Watatani, Yosaku, Yasuharu Sato, Kenji Nishida, Hiroaki Miyoshi, Yuichi Shiraishi, Kenichi Chiba, Tanaka Hiroko, et al. "Molecular Heterogeneity in Peripheral T-Cell Lymphoma Not Otherwise Specified Revealed By Comprehensive Mutational Profiling." Blood 128, no. 22 (December 2, 2016): 2927. http://dx.doi.org/10.1182/blood.v128.22.2927.2927.
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Abstract Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T-cells. Among them, PTCL-not otherwise specified (PTCL-NOS) is a diagnosis of exclusion, comprising the largest fraction of PTCL with a diverse underlying pathogenesis. Recently, the concept of nodal T-cell lymphomas with T-follicular helper (TFH) phenotype, including angioimmunoblastic T-cell lymphoma (AITL) and PTCL-NOS that manifests a TFH phenotype, has been proposed, a distinguishing feature of which is the high frequency of TET2, IDH2, DNMT3A, and RHOA(G17V) mutations. Although recent large-scale genetic studies have uncovered mutational landscapes of several other subtypes of PTCLs, such as cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma (ATL), the entire picture of somatic alterations in PTCL-NOS still remains elusive. In addition, their similarities and differences among various histological subtypes in PTCLs have not been fully elucidated. To address this issue, we initially analyzed our and publicly available whole-exome/genome as well as transcriptome sequencing data from PTCL-NOS and other related PTCLs. Then, we carried out an extensive investigation of somatic mutations and structural variations (SVs) in PTCL-NOS using targeted-capture sequencing of 118 PTCL-NOS samples. Consistent with previous reports, TET2 (35%) was the most frequently mutated gene in PTCL-NOS with the majority (78%) affected by multiple mutations, followed by RHOA (25%), TP53 (16%), KMT2C (12%), PLCG1 (12%), and HLA-B (11%). Besides them, a considerable proportion of patients harbored mutations in components of T-cell receptor (TCR) /NF-κB pathway (such as PRKCB, CARD11, IRF4, and PRDM1), other signal transduction molecules (STAT3, NOTCH1, and SOCS1), chemokine receptors (CCR4 and CCR7), epigenetic modifiers (CREBBP, KDM6A, IDH2, and DNMT3A), transcriptional regulators (GATA3 and TBL1XR1), and molecules associated with immune evasion (HLA-A, HLA-B, FAS, B2M, and CD58). In addition to deteriorating SVs involving frequently affected genes (TP53, FAS, GATA3, and TBL1XR1), we discovered several genes almost exclusively affected by SVs, including TP73, IKZF2, and NFKB2, and CD274. Novel targets of recurrent mutation were also identified, including PDCD1, YTHDF2, and LRP1B, which were frequently targeted by nonsense and frameshift mutations distributed throughout the entire genes. Among them, PDCD1encodes PD-1 receptor transmitting an inhibitory signal from PD-L1 and PD-L2 ligands in T cells, and its loss of function seems to enable tumor cells to escape from the suppression by this negative signal. Although the roles of YTHDF2, a reader protein of N6-methyladenosine, and LRP1B, a member of the low density lipoprotein receptor family, in T cells are not immediately apparent, these findings shed light on a new biological function of these genes. Next, we investigated the co-existence relationship between frequently altered genes in PTCL-NOS. Interestingly, mutations characteristic of TFH lymphomas (TET2, RHOA, IDH2, and DNMT3A) tended to co-occur in a subset of PTCL-NOS cases, whereas they were almost mutually exclusive with mutations in TP53 and TCR/NF-κB pathway genes. This observation reveals the molecular distinction between TFH and non-TFH lymphomas in PTCL-NOS: the former is similar to AITL, although TET2 mutations did not show higher allelic burden than RHOA and IDH2mutations. In contrast, the latter is at least partly characterized by the genetic alterations shared with ATL. In summary, our findings illuminate the landscape of somatic alterations in PTCL-NOS and provide a novel insight into their genetic and molecular heterogeneity, which would help us to exploit a new therapeutic strategy to combat this disease. Disclosures Ohshima: CHUGAI PHARMACEUTICAL CO.,LTD.: Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding, Speakers Bureau. Ogawa:Kan research institute: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding. Kataoka:Kyowa Hakko Kirin: Honoraria; Yakult: Honoraria; Boehringer Ingelheim: Honoraria.
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Zhou, Rong-Fu, Hong Tao, Jian Ouyang, Xian Zhang, Yonggong Yang, QiGuo Zhang, Jingyan Xu, and Bing Chen. "Molecular Diagnosis of One Pedigree with Protein S Deficiency and Antithrombin Deficiency." Blood 120, no. 21 (November 16, 2012): 5140. http://dx.doi.org/10.1182/blood.v120.21.5140.5140.
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Abstract Abstract 5140 Objective To identify gene mutations for one patient and his family members with protein S and antithrombin deficiency. Methods ELISA were used to detect protein S (PS), protein C (PC) and antithrombin (AT) activities for the proband and family members, respectively. The genomic DNA was extracted from the peripheral blood of proband and family members. All exons and their flanks of protein S gene and antithrombin gene were amplified by polymerase chain reaction (PCR). The PCR products were sequenced directly. The mutation-related exons of his famliy members were amplified by PCR and sequenced directly. Results The proband was a 49-year-old male. He presented with sudden left lower extremity swelling and pain without casues. Regular examination revealed that his APTT, PT, and TT were all in normal levels, but D- dimmer was 5. 62mg/L, Color doppler ultrasonography showed thrombosis in his left femoral vein. The activity of PS for his family members was ‡1 0%, ‡2 0%, ‡3 0%, ‡4 130. 8%, ‡5 8. 4%, ‡1 0%, ‡2 0%, and that of AT was ‡1 129. 1%, ‡2 51. 9%, ‡3 73.2%, ‡4 119. 1%, ‡5 136. 2%, ‡1 65. 5% and ‡2 60. 1%, respectively. The sequencing analysis showed that a heterozygous missense mutation G68395T (NG_009813. 1) was detected in Exon 4 of PS gene leading to the substitution of Arg90 by Leu (NP_000304. 2) for the propositus. The heterozygous mutation (Arg90Leu) was also found in other family members. A heterozygous (nonsense) mutation G12444A (NG_012462. 1) was detected in Exon 4 of AT gene leading to Trp257Ter (NP_000479. 1) for the propositus. The mutation (Trp257Ter) was found in other family members with reduced activity of AT. These two mutations (G68395T in PS gene and G12444A in AT gene) were not reported before and were thus novel ones. Conclusion The novel mutation G68395T in PS gene and G12444A in AT gene might be the causes of deficiency of PS and AT for the family. Disclosures: No relevant conflicts of interest to declare.
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Huang, Yanxia, Lamei Yuan, Yanna Cao, Renhong Tang, Hongbo Xu, Ziqian Tang, and Hao Deng. "Novel compound heterozygous mutations in the CHST6 gene cause macular corneal dystrophy in a Han Chinese family." Annals of Translational Medicine 9, no. 8 (April 2021): 622. http://dx.doi.org/10.21037/atm-20-7178.
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Austin, Stephen J., Mandy F. Gilkes, Ken I. Mills, and Alan K. Burnett. "Gene Expression Profiling of MLL-PTD in AML Identifies Differentially Regulated Members of the HOX Gene Family." Blood 106, no. 11 (November 16, 2005): 4358. http://dx.doi.org/10.1182/blood.v106.11.4358.4358.
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Abstract Partial tandem duplications (PTD) of the mixed lineage leukaemia (MLL) gene occur in approximately 7% of acute myeloid leukaemia (AML) patients. MLL-PTD has a frequency of approximately 10% in patients with normal karyotype and is reported to be associated with an adverse prognosis. Recent papers have reported that MLL-PTD may be useful as a marker for minimal residual disease (MRD) in AML patients with no other markers available due to normal cytogenetics. Diagnostic RNA from 133 AML patients was analysed for the presence of the MLL-PTD, twelve samples were positive and three of the twelve were also positive for FLT3 ITD. The MLL-PTD gene dosage was verified using quantitative polymerase chain reaction (QPCR). In order to identify the molecular disruption caused by MLL PTD mutations, fifty-four of the 133 patients were profiled using the Affymetrix U133A chip containing 22,283 probe sets. Four of the 54 samples analysed were MLL-PTD positive and three of these contained FLT3 mutations. Groups of genes were identified that had significance to MLL and showed more than 2-fold change in regulation in the MLL-PTD compared with wild type. Up-regulated genes found common to the two groups include HOXA9, HOX2B, HOX2C, HOX1 and CREBBP/EP 300. Whilst significant genes down-regulated more than 2-fold in MLL-PTD include MONDOA, a transcriptional activator. To identify whether MLL-PTD and FLT3 mutations used a common pathway, a comparison was made between genes with significance to either MLL-PTD or FLT3 mutations and no common genes were found. Hierarchical cluster analysis on the most significant genes, using Genespring software, created 4 main groups and distinguishes non-leukaemic samples, AML patients with MLL-PTD and those with a wild type MLL gene. This gene signature showed that MLL- PTD is a unique entity and could be identified amongst other AML subtypes. Moreover, over expression of Hox genes plays a role in MLL PTD positive AMLs and may provide an insight into the mechanism of the MLL-PTD with potential clinical implications.
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Uckun, Fatih M., and Sanjive Qazi. "Tyrosine kinases in KMT2A/MLL-rearranged acute leukemias as potential therapeutic targets to overcome cancer drug resistance." Cancer Drug Resistance 5, no. 10 (2022): 902–16. http://dx.doi.org/10.20517/cdr.2022.78.
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Aim: The main goal of this study was to elucidate at the transcript level the tyrosine kinase expression profiles of primary leukemia cells from mixed lineage leukemia 1 gene rearranged (KMT2A/MLL-R+) acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Methods: We evaluated protein tyrosine kinase (PTK) gene expression profiles of primary leukemic cells in KMT2A/MLL-R+ AML and ALL patients using publicly available archived datasets. Results: Our studies provided unprecedented evidence that the genetic signatures of KMT2A/MLL-R+ AML and ALL cells are characterized by transcript-level overexpression of specific PTK. In infants, children and adults with KMT2A/MLL-R+ ALL, as well as pediatric patients with KMT2A/MLL-R+ AML, the gene expression levels for FLT3, BTK, SYK, JAK2/JAK3, as well as several SRC family PTK were differentially amplified. In adults with KMT2A/MLL-R+ AML, the gene expression levels for SYK, JAK family kinase TYK2, and the SRC family kinases FGR and HCK were differentially amplified. Conclusion: These results provide new insights regarding the clinical potential of small molecule inhibitors of these PTK, many of which are already FDA/EMA-approved for other indications, as components of innovative multi-modality treatment platforms against KMT2A/MLL-R+ acute leukemias.
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Chakrabarty, P. K., Y. P. Duan, and D. W. Gabriel. "Cloning and Characterization of a Member of the Xanthomonas avr/pth Gene Family That Evades All Commercially Utilized Cotton R Genes in the United States." Phytopathology® 87, no. 11 (November 1997): 1160–67. http://dx.doi.org/10.1094/phyto.1997.87.11.1160.
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The highly virulent African strains of Xanthomonas campestris pv. malvacearum are quarantined pathogens in the United States and can evade or overcome all commercially utilized resistance (R) genes in cotton grown in the United States including the entire set of host differential lines used to distinguish 19 races of the pathogen. Nevertheless, the African strains carry multiple DNA fragments that strongly hybridize with members of the Xanthomonas avirulence (avr)/pathogenicity (pth) gene family. Since all previously tested members of the gene family confer avirulence against one or more R genes in cotton, strains carrying multiple members might not be expected to evade so many different R genes. The hybridizing DNA fragments were cloned from African strain XcmN and found to confer water-soaking ability to a nearly asymptomatic mutant strain of the pathogen. Restriction mapping, Southern hybridization, and DNA sequencing of the cloned fragments from XcmN were used to identify two water-soaking genes, pthN and pthN2, as new members of the Xanthomonas avr/pth gene family. The complete DNA sequence of pthN was obtained, and it is >94% identical with all other sequenced members of the gene family. Gene fusions of pthN with avrb6 (another family member) and other experiments revealed that the ability of African strain XcmN to water-soak cotton and avoid recognition by commercially used cotton R genes is determined by the specific repeats of multiple functional members of the Xanthomonas avr/pth gene family.
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Zaugg, Christophe, Margarete Borg-von Zepelin, Utz Reichard, Dominique Sanglard, and Michel Monod. "Secreted Aspartic Proteinase Family ofCandida tropicalis." Infection and Immunity 69, no. 1 (January 1, 2001): 405–12. http://dx.doi.org/10.1128/iai.69.1.405-412.2001.
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ABSTRACT Medically important yeasts of the genus Candida secrete aspartic proteinases (Saps), which are of particular interest as virulence factors. Like Candida albicans, Candida tropicalis secretes in vitro one dominant Sap (Sapt1p) in a medium containing bovine serum albumin (BSA) as the sole source of nitrogen. Using the gene SAPT1 as a probe and under low-stringency hybridization conditions, three new closely related gene sequences, SAPT2 to SAPT4, encoding secreted proteinases were cloned from a C. tropicalis λEMBL3 genomic library. All bands identified by Southern blotting ofEcoRI-digested C. tropicalis genomic DNA withSAPT1 could be assigned to a specific SAP gene. Therefore, the SAPT gene family of C. tropicalis is likely to contain only four members. Interestingly, the SAPT2 and SAPT3 gene products, Sapt2p and Sapt3p, which have not yet been detected in C. tropicaliscultures in vitro, were produced as active recombinant enzymes with the methylotrophic yeast Pichia pastoris as an expression system. As expected, reverse transcriptase PCR experiments revealed a strong SAPT1 signal with RNA extracted from cells grown in BSA medium. However, a weak signal was obtained with all otherSAPT genes under several conditions tested, showing that these SAPT genes could be expressed at a basic level. Together, these experiments suggest that the gene products Sapt2p, Sapt3p, and Sapt4p could be produced under conditions yet to be described in vitro or during infection.
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Li, Xiaolan, Honghong He, Han Wang, Xinquan Wu, Hong Wang, and Juan Mao. "Identification and expression analysis of the AHL gene family in grape (Vitis vinifera)." Plant Gene 26 (June 2021): 100285. http://dx.doi.org/10.1016/j.plgene.2021.100285.
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Ding, Tingbo, Inamul Kabir, Yue Li, Caixia Lou, Amirfarbod Yazdanyar, Jiachen Xu, Jibin Dong, et al. "All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity." Journal of Lipid Research 56, no. 3 (January 20, 2015): 537–45. http://dx.doi.org/10.1194/jlr.m054627.
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Lai, Binbin, Yanli Lai, Yanli Zhang, Miao Zhou, Lixia Sheng, and Guifang OuYang. "The Solute Carrier Family 2 Genes Are Potential Prognostic Biomarkers in Acute Myeloid Leukemia." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303381989430. http://dx.doi.org/10.1177/1533033819894308.
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Aims: The solute carrier family 2 (SLC2) genes are comprised of 14 members which are essential for the maintenance of glucose uptake and survival of tumour cells. This study was performed to investigate the associations of SLC2 family gene expression with mortality in acute myeloid leukemia (AML). Methods: Clinical features and SLC2 family gene expression data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus database. The associations between SLC2 family gene expression and clinicopathologic features were analyzed using linear regression model. Kaplan-Meier survival, univariate, multivariate survival analyses and validation analysis were performed to analyze the associations between SLC2 family gene expression and patients’ overall survival. Results: Patient mortality was positively associated with age and cytogenetic risk in AML patients. Kaplan-Meier survival analysis suggested that patients with high SLC2A5 and SLC2A10 expression showed poorer survival than those with low SLC2A5 and SLC2A10 expression. In contrast, patients with high SLC2A13 expression exhibited better prognosis than those with low SLC2A13 expression ( P < 0.05 for all cases, log rank test). Multivariate survival analysis and validation analysis confirmed that high expression of SLC2A5 and SLC2A10 and low expression of SLC2A13 were associated with increased mortality ( P = 0.00, Odd ratio [OR]:4.05, 95% Confidence Interval [CI]: 1.73-10.22; P = 0.00, OR: 3.66, 95% CI: 1.54-9.25; and P = 0.01, OR: 0.26, 95% CI: 0.09-0.68, respectively). Conclusion: SLC family gene expression, such as SLC2A5, SLC2A10 and SLC2A13, was significantly associated with prognosis of AML patients, their expression levels might become useful prognostic biomarkers in AML.
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Sadzevičienė, Ieva, Olga Liaugaudienė, Justinas Besusparis, Jolita Asadauskienė, Ilona Kulikienė, Birutė Brasiūnienė, Rasa Sabaliauskaitė, and Sonata Jarmalaitė. "Recurrent Germline BRCA2 Gene Mutation in Lithuanian Family." Medicina 56, no. 3 (March 10, 2020): 119. http://dx.doi.org/10.3390/medicina56030119.
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Approximately 10% of all breast cancer (BC) cases are familial and caused by inheritance of mutant BRCA1, BRCA2, or some other genes from the same DNA reparation pathway. Genetic counseling in families with cancer history is a powerful means for early cancer detection and active risk reduction through preventive interventions. This is the first report of the rare inherited BRCA2 frameshift-deletion mutation c.3847_3848delGT in one Lithuanian pedigree with the intense familial history of BC. Three BRCA2-positive blood relatives with BC of different biological types were identified in this pedigree with the same type mutation. All three cases were diagnosed with advanced stage ductal carcinoma. Markedly, polymorphic cells and numerous mitoses were identified in BC from the cases. Two patients from the family were diagnosed with the triple negative tumors, while one case had early onset of the hormone positive BC. Despite the variation in clinical and biological presentation of BC, all cases showed a good response to conventional treatment. In conclusion, the strong influence of BRCA2 mutation on the onset of BC of various biological types reveals the complexity of genetic counselling in families with BC history.
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Mohr, Toni, James Horstman, Yong Q. Gu, Nagwa I. Elarabi, Naglaa A. Abdallah, and Roger Thilmony. "CRISPR-Cas9 Gene Editing of the Sal1 Gene Family in Wheat." Plants 11, no. 17 (August 30, 2022): 2259. http://dx.doi.org/10.3390/plants11172259.
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The highly conserved Sal1 encodes a bifunctional enzyme with inositol polyphosphate-1-phosphatase and 3′ (2′), 5′-bisphosphate nucleotidase activity and has been shown to alter abiotic stress tolerance in plants when disrupted. Precise gene editing techniques were used to generate Sal1 mutants in hexaploid bread wheat. The CRISPR (Clustered Regulatory Interspaced Short Palindromic Repeats) Cas9 system with three guide RNAs (gRNAs) was used to inactivate six Sal1 homologous genes within the Bobwhite wheat genome. The resulting mutant wheat plants with all their Sal1 genes disabled had slimmer stems, had a modest reduction in biomass and senesced more slowly in water limiting conditions, but did not exhibit improved yield under drought conditions. Our results show that multiplexed gRNAs enabled effective targeted gene editing of the Sal1 gene family in hexaploid wheat. These Sal1 mutant wheat plants will be a resource for further research studying the function of this gene family in wheat.
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van Leeuwen, Frank N., Joost Casper van Galen, Roland P. Kuiper, Liesbeth van Emst, Marloes R. Levers, Esther Tijchon, Blanca Scheijen, et al. "BTG1, a Gene Frequently Deleted in Pre-B ALL, Controls Glucocorticoid Receptor-Mediated Gene Expression." Blood 114, no. 22 (November 20, 2009): 3458. http://dx.doi.org/10.1182/blood.v114.22.3458.3458.
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Abstract Abstract 3458 Poster Board III-346 Background By genome wide profiling we have found that about 10 % of pediatric pre-B ALL cases contain a (single copy) deletion of the B cell translocation gene 1 (BTG1) gene. BTG1 belongs to a family of potential tumor suppressor genes, which include BTG2, BTG3, TOB and TOB2. Proteins encoded by members of this gene family have been implicated in the induction of growth arrest or apoptosis in a variety of model systems. Moreover, BTG1 associates with and regulates the activity of the arginine methyl transferase PRMT1, a coactivator of nuclear receptor-mediated transcription. Hence we hypothesized that loss of BTG1 function, for instance due to deletion, may affect glucocorticoid induced therapy responses in ALL. Results Using RNA interference, we find that loss of BTG1 expression decreases sensitivity of pre-B ALL cells to the apoptosis-inducing effects of synthetic GCs about 10,000 fold (Figure). This acquired GC resistance is accompanied by a greater than 10 fold reduction in GR protein expression as well as a (near complete) loss of GC-induced gene expression. Conversely, re-expression of BTG1 restores GC sensitivity by potentiating GC-induced GR expression. By chromatin immunoprecipitations using anti PRMT1 antibodies we show that PRMT1 is recruited to the GR gene promoter in a BTG1-dependent manner, consistent with a role for this arginine methyl transferase in the regulation of GR-mediated gene expression. Conclusions Together, our results demonstrate the importance of the BTG1/PRMT1 complex in regulating GR-mediated gene expression and reveal how deregulation of the this complex can give rise to GC resistance. Targeting of these coactivators as part of the GR regulatory circuitry could offer novel opportunities for improving the efficacy of GC based therapies in ALL as well as other hematological malignancies. Disclosures No relevant conflicts of interest to declare.
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Ren, Junxiao, Naiyi Xu, Zheng Ma, Yanmin Li, Cuicui Li, Yanbin Wang, Yadong Tian, Xiaojun Liu, and Xiangtao Kang. "Characteristics of expression and regulation of sirtuins in chicken (Gallus gallus)." Genome 60, no. 5 (May 2017): 431–40. http://dx.doi.org/10.1139/gen-2016-0125.
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Sirtuins (SIRT1–SIRT7) are a family of NAD+-dependent protein deacetylases that are linked to post-translational regulation of many metabolic processes. There are few reports available for chicken sirtuins (designated cSIRT1–cSIRT7), whose expression and regulation in the liver have yet to be explored. In the present study, we characterized the expression and regulation of sirtuin family members in chicken liver. The results showed that the sirtuin family members in chicken share the same conserved functional SIR2 domains. All the sirtuin family members were expressed extensively in all tissues examined, and the expression levels of cSIRT1, cSIRT2, cSIRT4, cSIRT6, and cSIRT7 in the liver increased significantly with sexual maturity. However, all sirtuin family members were downregulated (P < 0.05) in chicken livers and cultured primary hepatocytes treated with 17β-estradiol. We concluded that the expression levels of some chicken sirtuin family members in the liver were upregulated with sexual maturation, but might not be regulated directly by estrogen. Whereas estrogen could be used as an inhibitor of all sirtuins, both in vivo and in vitro.
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Brouta, Frédéric, Frédéric Descamps, Michel Monod, Sandy Vermout, Bertrand Losson, and Bernard Mignon. "Secreted Metalloprotease Gene Family of Microsporum canis." Infection and Immunity 70, no. 10 (October 2002): 5676–83. http://dx.doi.org/10.1128/iai.70.10.5676-5683.2002.
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ABSTRACT Keratinolytic proteases secreted by dermatophytes are likely to be virulence-related factors. Microsporum canis, the main agent of dermatophytosis in dogs and cats, causes a zoonosis that is frequently reported. Using Aspergillus fumigatus metalloprotease genomic sequence (MEP) as a probe, three genes (MEP1, MEP2, and MEP3) were isolated from an M. canis genomic library. They presented a quite-high percentage of identity with both A. fumigatus MEP and Aspergillus oryzae neutral protease I genes. At the amino acid level, they all contained an HEXXH consensus sequence, confirming that these M. canis genes (MEP genes) encode a zinc-containing metalloprotease gene family. Furthermore, MEP3 was found to be the gene encoding a previously isolated M. canis 43.5-kDa keratinolytic metalloprotease, and was successfully expressed as an active recombinant enzyme in Pichia pastoris. Reverse transcriptase nested PCR performed on total RNA extracted from the hair of M. canis-infected guinea pigs showed that at least MEP2 and MEP3 are produced during the infection process. This is the first report describing the isolation of a gene family encoding potential virulence-related factors in dermatophytes.
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Garbino, Alejandro, Ralph J. van Oort, Sayali S. Dixit, Andrew P. Landstrom, Michael J. Ackerman, and Xander H. T. Wehrens. "Molecular evolution of the junctophilin gene family." Physiological Genomics 37, no. 3 (May 2009): 175–86. http://dx.doi.org/10.1152/physiolgenomics.00017.2009.
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Junctophilins (JPHs) are members of a junctional membrane complex protein family important for the physical approximation of plasmalemmal and sarcoplasmic/endoplasmic reticulum membranes. As such, JPHs facilitate signal transduction in excitable cells between plasmalemmal voltage-gated calcium channels and intracellular calcium release channels. To determine the molecular evolution of the JPH gene family, we performed a phylogenetic analysis of over 60 JPH genes from over 40 species and compared conservation across species and different isoforms. We found that JPHs are evolutionary highly conserved, in particular the membrane occupation and recognition nexus motifs found in all species. Our data suggest that an ancestral form of JPH arose at the latest in a common metazoan ancestor and that in vertebrates four isoforms arose, probably following two rounds of whole genome duplications. By combining multiple prediction techniques with sequence alignments, we also postulate the presence of new important functional regions and candidate sites for posttranslational modifications. The increasing number of available sequences yields significant insight into the molecular evolution of JPHs. Our analysis is consistent with the emerging concept that JPHs serve dual important functions in excitable cells: structural assembly of junctional membrane complexes and regulation of intracellular calcium signaling pathways.
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Porter, Mary E., Julie A. Knott, Steven H. Myster, and Samuel J. Farlow. "The Dynein Gene Family in Chlamydomonas reinhardtii." Genetics 144, no. 2 (October 1, 1996): 569–85. http://dx.doi.org/10.1093/genetics/144.2.569.
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Abstract To correlate dynein heavy chain (Dhc) genes with flagellar mutations and gain insight into the function of specific dynein isoforms, we placed eight members of the Dhc gene family on the genetic map of Chlamydomonas. Using a PCR-based strategy, we cloned 11 Dhc genes from Chlamydomonas. Comparisons with other Dhc genes indicate that two clones correspond to genes encoding the alpha and beta heavy chains of the outer dynein arm. Alignment of the predicted amino acid sequences spanning the nucleotide binding site indicates that the remaining nine clones can be subdivided into three groups that are likely to include representatives of the inner-arm Dhc isoforms. Gene-specific probes reveal that each clone represents a single-copy gene that is expressed as a transcript of the appropriate size (>13 kb) sufficient to encode a high molecular weight Dhc polypeptide. The expression of all nine genes is upregulated in response to deflagellation, suggesting a role in axoneme assembly or motility. Restriction fragment length polymorphisms between divergent C. reinhardtii strains have been used to place each Dhr gene on the genetic map of Chlamydomonas. These studies lay the groundwork for correlating defects in different Dhc genes with specific flagellar mutations.
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Gutierrez, Javier, Roy Platt, Juan C. Opazo, David A. Ray, Federico Hoffmann, and Michael Vandewege. "Evolutionary history of the vertebrate Piwi gene family." PeerJ 9 (November 5, 2021): e12451. http://dx.doi.org/10.7717/peerj.12451.
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PIWIs are regulatory proteins that belong to the Argonaute family. Piwis are primarily expressed in gonads and protect the germline against the mobilization and propagation of transposable elements (TEs) through transcriptional gene silencing. Vertebrate genomes encode up to four Piwi genes: Piwil1, Piwil2, Piwil3 and Piwil4, but their duplication history is unresolved. We leveraged phylogenetics, synteny and expression analyses to address this void. Our phylogenetic analysis suggests Piwil1 and Piwil2 were retained in all vertebrate members. Piwil4 was the result of Piwil1 duplication in the ancestor of gnathostomes, but was independently lost in ray-finned fishes and birds. Further, Piwil3 was derived from a tandem Piwil1 duplication in the common ancestor of marsupial and placental mammals, but was secondarily lost in Atlantogenata (Xenarthra and Afrotheria) and some rodents. The evolutionary rate of Piwil3 is considerably faster than any Piwi among all lineages, but an explanation is lacking. Our expression analyses suggest Piwi expression has mostly been constrained to gonads throughout vertebrate evolution. Vertebrate evolution is marked by two early rounds of whole genome duplication and many multigene families are linked to these events. However, our analyses suggest Piwi expansion was independent of whole genome duplications.
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Minnick, Michael F., Kate N. Sappington, Laura S. Smitherman, Siv G. E. Andersson, Olof Karlberg, and James A. Carroll. "Five-Member Gene Family of Bartonella quintana." Infection and Immunity 71, no. 2 (February 2003): 814–21. http://dx.doi.org/10.1128/iai.71.2.814-821.2003.
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ABSTRACT Bartonella quintana, the agent of trench fever and an etiologic agent of bacillary angiomatosis, has an extraordinarily high hemin requirement for growth compared to other bacterial pathogens. We previously identified the major hemin receptor of the pathogen as a 30-kDa surface protein, termed HbpA. This report describes four additional homologues that share approximately 48% amino acid sequence identity with hbpA. Three of the genes form a paralagous cluster, termed hbpCAB, whereas the other members, hbpD and hbpE, are unlinked. Secondary structure predictions and other evidence suggest that Hbp family members are β-barrels located in the outer membrane and contain eight transmembrane domains plus four extracellular loops. Homologs from a variety of gram-negative pathogens were identified, including Bartonella henselae Pap31, Brucella Omp31, Agrobacterium tumefaciens Omp25, and neisserial opacity proteins (Opa). Family members expressed in vitro-synthesized proteins ranging from ca. 26.5 to 35.1 kDa, with the exception of HbpB, an ∼55.9-kDa protein whose respective gene has been disrupted by a ∼510 GC-rich element containing variable-number tandem repeats. Transcription analysis by quantitative reverse transcriptase-PCR (RT-PCR) indicates that all family members are expressed under normal culture conditions, with hbpD and hbpB transcripts being the most abundant and the rarest, respectively. Mutagenesis of hbpA by allelic exchange produced a strain that exhibited an enhanced hemin-binding phenotype relative to the parental strain, and analysis by quantitative RT-PCR showed elevated transcript levels for the other hbp family members, suggesting that compensatory expression occurs.
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Branca, Malorye Allison. "All in the Family–NOT: Researchers ID Gene Variant that Protects against Alzheimer's Disease." Clinical OMICs 5, no. 1 (January 2018): 34–36. http://dx.doi.org/10.1089/clinomi.05.01.22.
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Gerl, Lydia, Rainer Deutzmann, and Manfred Sumper. "Halobacterial flagellins are encoded by a multigene family Identification of all five gene products." FEBS Letters 244, no. 1 (February 13, 1989): 137–40. http://dx.doi.org/10.1016/0014-5793(89)81179-2.
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Abe, Michiaki, Koji Nata, Takako Akiyama, Nausheen J. Shervani, Seiichi Kobayashi, Tomoko Tomioka-Kumagai, Sadayoshi Ito, Shin Takasawa, and Hiroshi Okamoto. "Identification of a novel Reg family gene, Reg IIIδ, and mapping of all three types of Reg family gene in a 75 kilobase mouse genomic region." Gene 246, no. 1-2 (April 2000): 111–22. http://dx.doi.org/10.1016/s0378-1119(00)00059-7.
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Zhao, Da, Zheng Chen, Lei Xu, Lijun Zhang, and Quan Zou. "Genome-Wide Analysis of the MADS-Box Gene Family in Maize: Gene Structure, Evolution, and Relationships." Genes 12, no. 12 (December 7, 2021): 1956. http://dx.doi.org/10.3390/genes12121956.
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The MADS-box gene family is one of the largest families in plants and plays an important roles in floral development. The MADS-box family includes the SRF-like domain and K-box domain. It is considered that the MADS-box gene family encodes a DNA-binding domain that is generally related to transcription factors, and plays important roles in regulating floral development. Our study identified 211 MADS-box protein sequences in the Zea mays proteome and renamed all the genes based on the gene annotations. All the 211 MADS-box protein sequences were coded by 98 expressed genes. Phylogenetic analysis of the MADS-box genes showed that all the family members were categorized into five subfamilies: MIKC-type, Mα, Mβ, Mγ, and Mδ. Gene duplications are regarded as products of several types of errors during the period of DNA replication and reconstruction; in our study all the 98 MADS-box genes contained 22 pairs of segmentally duplicated events which were distributed on 10 chromosomes. We compared expression data in different tissues from the female spikelet, silk, pericarp aleurone, ear primordium, leaf zone, vegetative meristem, internode, endosperm crown, mature pollen, embryo, root cortex, secondary root, germination kernels, primary root, root elongation zone, and root meristem. According to analysis of gene ontology pathways, we found a total of 41 pathways in which MADS-box genes in maize are involved. All the studies we conducted provided an overview of MADS-box gene family members in maize and showed multiple functions as transcription factors. The related research of MADS-box domains has provided the theoretical basis of MADS-box domains for agricultural applications.
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Bai, Xiangdong, Jiabao Ji, Wei Wang, Chenrui Gu, Qibin Yu, Jing Jiang, Chuanping Yang, and Guifeng Liu. "Characterization of CBL-Interacting Protein Kinases’ Gene Family and Expression Pattern Reveal Their Important Roles in Response to Salt Stress in Poplar." Forests 13, no. 9 (August 25, 2022): 1353. http://dx.doi.org/10.3390/f13091353.
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The CBL-interacting protein kinases’ (CIPKs) gene family plays an important role in plants under salt stress. In this study, a total of 31 PtrCIPK genes were identified in poplar. CIPKs’ gene family was divided into two categories, few intron classes and multi-intron classes. They all have the core components of the kinase domain and regulatory domain unique to the CIPK gene family and share most of the same motifs. PtrCIPKs have 17 fragment repeat events and have high homology with Arabidopsis thaliana and Betula platyphylla, and partial homology with Zea mays. Prediction of cis-acting elements found that the PtrCIPK gene family has the most elements in terms of stress. Under NaCl stress, all members of poplar CIPKs’ gene family were significantly expressed. There were fourteen up-regulated genes and four down-regulated genes. Candidate gene expression was significantly higher in the phloem than in other tissues. In this study, characterization of CBL-interacting protein kinases’ gene family and expression pattern reveal their important roles in response to salt stress in poplar.
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Wełnicka-Jaskiewicz, M., A. żaczek, K. P. Bielawski, J. Jańkiewicz, A. Badzio, W. Olszewski, K. Konopa, P. Rhone, E. Senkus-Konefka, and J. Jassem. "Gene copy numbers of HER family in breast cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 10544. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10544.
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10544 Background: Most clinicopathological analyses of HER alterations in breast cancer were limited to single HER family members. Since the activation of certain HER receptors is possible only as a result of their dimerization, determining the alterations of all four HER genes may be more relevant. The aim of the study was to estimate the frequency of disorders in all four HER genes, and to determine their correlation with the clinical and histological features in breast cancer patients. Methods: Gene copy number (GCN) of ERBB oncogenes was analyzed with double differential PCR (ddPCR) in a consecutive series of 225 breast cancer patients. Statistical analysis was performed with a set of nonparametric tests. Results: Amplifications of HER1, HER2, HER3 and HER4 were detected in 15%, 26%, 10% and 15% of cases respectively, and deletions in 31%, 2%, 2% and 7% cases respectively. Abnormal GCN of at least one, and at least two oncogenes was found in 65% and 31% of the tumors, respectively. Average GCNs of all HER oncogenes significantly correlated with each other. These correlations were particularly high for HER2/HER3, HER2/HER4 and HER3/HER4 (all p<10-8), and were much stronger in N(+) compared to N(-) tumors. HER1 deletions were associated with the lack of progesterone receptor (p=0.03), whereas HER3 and HER4 amplifications were more common in well differentiated tumors (p=0.03 and 0.047 respectively). At univariate analysis disease-free survival (DFS) and overall survival (OS) were related with T and N stage, and HER1 amplification. The multivariate analysis showed that DFS was influenced by T, N and HER1 amplification, whereas OS by T, N and tumor grade. Conclusions: Our results indicate a key role of HER heterodimers in tumor progression and confirm that HER2 is the preferred partner for other HER oncogenes in this process. Deletions of HER1 were associated with unfavourable characteristics, whereas HER3 and HER4 amplifications may be linked with less aggressive phenotypes. No significant financial relationships to disclose.
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Meek, R. L., and E. P. Benditt. "Amyloid A gene family expression in different mouse tissues." Journal of Experimental Medicine 164, no. 6 (December 1, 1986): 2006–17. http://dx.doi.org/10.1084/jem.164.6.2006.
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Serum amyloid A (SAA) is a major acute-phase reactant and apoprotein of high density lipoprotein (HDL). SAA is encoded by a family of three active genes. We examined hepatic expression and searched for extrahepatic expression of the three SAA mRNAs after injection with casein or LPS. Studies using an SAA cDNA, which detects all three SAA mRNAs, revealed that after casein injection liver SAA mRNA was elevated approximately 1,000-fold. Adrenal gland expressed SAA mRNA at a low level (0.5% of hepatic level), and was the only extrahepatic tissue with elevated SAA mRNA after casein injection. The small intestine, primarily the ileum, and the large intestine of unstimulated control animals contained 5- and 15-fold higher SAA mRNA levels than control liver. LPS also elevated liver SAA mRNA approximately 1,000-fold. However, in contrast to casein injection, every extrahepatic tissue examined expressed SAA mRNA. Lung and kidney contained 2-5% and large intestine contained nearly 10% of SAA mRNA levels found in liver RNA. SAA mRNA levels were lower in the remaining tissues and ranged from 0.1% in the brain and pancreas to 1.0% in the small intestine, with the ileum containing 50-fold more than the duodenum. Analysis of liver with SAA1, SAA2, and SAA3 mRNA-specific oligonucleotide probes revealed that SAA1 and SAA2 mRNA were elevated approximately 50-fold higher than SAA3 mRNA after casein administration. LPS, however, induced all three SAA mRNAs equally. In extrahepatic tissues, SAA1, SAA2, and SAA3 mRNAs were expressed differentially and can be grouped into three general classes: tissues expressing all three genes, tissues expressing SAA1 and SAA3, and tissues expressing predominantly or only SAA3.