We report two complete proviral genome sequences of human T-cell leukemia virus type 1 (HTLV-1) isolated from the peripheral blood specimens of acute type adult T-cell leukemia (ATL) patients in Oita ...Prefecture, Japan.
The human proto-oncogene BCL6 encodes a BTB/POZ-zinc finger transcriptional repressor that is required for germinal centre (GC) development and is expressed in the majority of normal GC B cells and ...in the majority of B cell lymphoma (B-NHL), including follicular lymphoma (FL) and a subset of diffuse large B cell lymphomas (DLBCLs). Deregulation of BCL6, by chromosomal translocation or somatic hypermutation, is implicated in the pathogenesis of B-NHL. The precise function of BCL6 in GC development and lymphomagenesis is still unclear also due to the very few direct BCL6 target genes that have been identified. In order to identify physiologically relevant BCL6 direct target genes, we used a novel approach combining high-throughput biochemical (ChIP-on-chip), bioinformatics (ARACNe) (Basso et al., Nature Genetics, 2005) and gene expression profile analysis (Klein et al., Proc. Natl. Acad. Sci., 2004) of normal GC B cells. The results (see abstract by Saito et al.) have identified a core of bona fide target genes whose promoter is bound by BCL6, whose transcription is dynamically linked to BCL6, and whose expression is down-regulated in GC B cells. Among the genes meeting these stringent criteria, we found BCL2, encoding the anti-apoptotic molecule whose expression is deregulated by chromosomal translocations or gene amplification in the majority of FL and in a subset of DLBCL. Further investigations showed that BCL6 represses BCL2 transcription by binding specific DNA sites within the BCL2 promoter region. Suppression of BCL6 expression via specific siRNAs leads to increased levels of BCL2, and, conversely, constitutive BCL6 expression prevents B cell receptor (BCR)-induced upregulation of BCL2 in B cells. Consistent with a physiological role for BCL6- mediated BCL2 suppression, immunohistochemical analysis shows that BCL2 expression is absent in GC B cells where BCL6 is highly expressed. Notably, the comparative analysis of BCL6 and BCL2 expression in B-NHL cell lines showed a conserved inverse correlation between BCL6 and BCL2 levels in cell lines carrying a normal BCL2 locus. However, cell lines carrying chromosomal translocations or amplifications affecting the BCL2 gene displayed the pathologic co-expression of both proteins, suggesting that the alterations affecting the BCL2 locus prevent BCL6-mediated suppression. These results indicate that one critical role of BCL6 is the modulation of antiapoptotic function in GC B cells via BCL2 transcriptional repression, suggesting a mechanism by which B cells may die in the GC if not rescued by BCR and CD40 engagement, both of which downregulate BCL6 while inducing BCL2 expression. Alterations of the BCL2 locus may contribute to lymphomagenesis by making the gene resistant to suppression by BCL6, and therefore allowing B cells to avoid apoptosis in the absence of antigen- and T-cell-mediated rescue.
BCL6 is a transcriptional repressor required by mature B cells for germinal center (GC) formation, whose deregulated expression, through mutations and translocations, is implicated in ...lymphomagenesis. The normal function of BCL6 is only partially known since a limited number of direct target genes have been identified by the analysis of cell lines derived from GC-derived lymphomas. However, the complete set of targets functionally relevant for the role of BCL6 in normal GC B cell physiology has not been completely uncovered and the possibility that BCL6 function may be altered in transformed cells has not been excluded. To address these issues, we used an integrated biochemical/computational/functional approach including:
identification of BCL6-bound promoters by genome-wide chromatin immunoprecipitation (ChIP-chip) in normal human GC B cells;a computational algorythm inferring transcriptional relationships starting from gene expression data (ARACNe, Basso et al. Nature Genetics 2005);validation of physiologic relevance of the candidate target genes by selection of those either not expressed in normal GC B cells or downregulated compared to pre- and post- GC B cells.
This approach identified a set of 1,207 genes which were then subjected to pathway analysis using several databases. The results showed that BCL6 regulates important signaling pathways via direct transcriptional repression of multiple genes acting at different levels from the cell surface (receptors), through signaling molecules to the nucleus. These pathways include:
apoptosis, by impairing the expression of both pro- and anti-apoptotic molecules including several TNF-type receptors, signaling molecules (e.g. TRADD, A20, XIAP, TOSO) and effectors (e.g. CASP8);JAK-STAT signaling, through the repression of multiple interleukin and interferon receptors and the transcription factors STAT1, STAT3 and STAT5A;B cell receptor signaling, via repression of signaling molecules (e.g. lyn, vav), several MAP kinases, and transcription factors (e.g. JUN and NF-kB components);Toll-like receptor signaling, by regulating receptors (e.g. TLR1, 7 and 9);DNA damage sensing and response (e.g. TP53BP1, ATM).
Overall, these results provide a comprehensive picture of BCL6 function suggesting that one role of BCL6 is to prevent GC centroblasts from receiving activation and differentiation signals before completion of the phase of proliferative expansion and somatic hypermutation leading to their selection based on antibody affinity maturation.
The BCL6 proto-oncogene encodes a transcriptional repressor that is required for germinal center (GC) formation and whose deregulation by genomic lesions is implicated in the pathogenesis of ...GC-derived diffuse large B cell lymphoma (DLBCL) and, less frequently, follicular lymphoma (FL). The biological function of BCL6 is only partially understood because no more than a few genes have been functionally characterized as direct targets of BCL6 transrepression activity. Here we report that the anti-apoptotic proto-oncogene BCL2 is a direct target of BCL6 in GC B cells. BCL6 binds to the BCL2 promoter region by interacting with the transcriptional activator Miz1 and suppresses Miz1-induced activation of BCL2 expression. BCL6-mediated suppression of BCL2 is lost in FL and DLBCL, where the 2 proteins are pathologically coexpressed, because of BCL2 chromosomal translocations and other mechanisms, including Miz1 deregulation and somatic mutations in the BCL2 promoter region. These results identify an important function for BCL6 in facilitating apoptosis of GC B cells via suppression of BCL2, and suggest that blocking this pathway is critical for lymphomagenesis.
Deregulated expression of the proto-oncogenes BCL6 and c-MYC caused by chromosomal translocation or somatic hypermutation is common in non-Hodgkin B cell lymphoma derived from germinal center (GC) B ...cells, including diffuse large cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Normal GC B cells express BCL6, whereas, surprisingly, they do not express c-MYC, suggesting that the expression of this oncogene in BL and DLBCL (20% of cases) is ectopic (Klein, U. et al. Proc Natl Acad Sci U S A 100, 2639–2644, 2003). Here we report that c-MYC is absent in proliferating GC B cells because it is transcriptionally suppressed by BCL6, as demonstrated by the presence of specific BCL6 binding sites in the c-MYC promoter region and by chromatin immunoprecipitation experiments showing that BCL6 is bound to these sites in vivo. Thus, c-MYC escapes BCL6-mediated suppression in lymphoma leading to the co-expression of the two transcription factors, an event never observed in immunohistochemical and gene expression profile analysis of normal GC B cells. Surprisingly, co-immunoprecipitation experiments and in vitro binding experiments indicate that, when co-expressed, BCL6 and c-MYC are physically bound in a novel complex detectable in DLBCL and BL cell lines as well as in primary lymphoma cases. The formation of the BCL6/c-MYC complex has several significant functional consequences on the function of both c-MYC and BCL6: 1) a two fold, BCL6-binding dependent increase in c-MYC half-life, an event that has been shown to contribute to its oncogenic activation; 2) a synergistic increase in the ability of both BCL6 and c-MYC to suppress MIZ1-activated transcription of the p21CIP cell cycle arrest gene; 3) MYC-dependent inhibition of BCL6 acetylation by p300, an event that physiologically inactivates BCL6 via c-MYC-mediated recruitment of HDAC. Notably, the pathologic co-expression of c-MYC and BCL6 was shown to have pathologic consequences in vivo, since double transgenic BCL6/c-MYC mice display accelerated lymphoma development and the appearance of a novel GC-derived tumor phenotype not recognizable in single transgenic animals and containing the pathologic c-MYC/BCL6 complex. Thus, the pathologic co-expression and illegitimate physical interaction of BCL6 and c-MYC leads to an increase in the constitutive activity of both oncogenes. These results identify a novel mechanism of oncogenic function for BCL6 and c-MYC and a novel tumor-specific protein complex of potential therapeutic interest.
The proto-oncogene BCL6 encodes a BTB/POZ-zinc finger transcriptional repressor that is necessary for germinal center (GC) formation and is implicated in the pathogenesis of B-cell lymphoma. In ~50% ...diffuse large cell lymphoma and 10% follicular lymphoma, BCL6 gene expression is deregulated by chromosomal translocations or mutations that affect its 5′ regulatory region. The precise function of BCL6 in GC development and lymphomagenesis is unclear since very few BCL6 direct target genes have been identified. We report that BCL6 suppresses p53-dependent and p53-indepenent growth arrest and apoptosis responses in GC B cells. BCL6 directly suppresses the transcription of the p53 gene, as demonstrated by (1) chromatin immunoprecipitation (ChIP) assays showing that BCL6 binds the p53 promoter region in vivo; and (2) transient transfection/reporter assays identifying within the p53 promoter region two BCL6-binding sites that mediate BCL6-mediated suppression of p53 transcription.
Accordingly, suppression of BCL6 expression via specific siRNA leads to increased expression of p53 both under basal condition and in response to DNA damage. Consistent with a physiological role for BCL6-mediated p53 suppression, immunohistochemical analysis shows that p53 expression is absent in GC B cells where BCL6 is highly expressed. In addition, our data reveal that BCL6 inhibits the p53-independent activation of the p21/WAF1 cell cycle arrest gene by binding to Miz-1, a transcription factor involved in p21 activation. Consistent with a role of BCL6 in inhibiting p53-related cell cycle arrest and apoptotic responses, constitutive expression of BCL6 suppresses p53 expression and p53-target genes (P21 and PUMA) and protects B cell lines from apoptosis induced by DNA damage. These results indicate that one function of BCL6 is to allow GC B cells (centroblasts) to constitutively proliferate and to sustain the physiologic DNA breaks required for immunoglobulin switch recombination and somatic hypermutation without inducing p53-related responses. These findings also imply that B cell lymphoma with deregulated BCL6 expression are functionally p53-negative and impaired in apoptotic responses.
Abstract
We have developed a method to make a spectral-line-based survey of hot cores, which represent an important stage of high-mass star formation, and applied the method to the data of the FUGIN ...(FOREST Unbiased Galactic plane Imaging survey with the Nobeyama 45 m telescope) survey. First, we select hot core candidates by searching the FUGIN data for the weak hot core tracer lines (HNCO and CH3CN) by stacking, and then we conduct follow-up pointed observations on these candidates in C34S, SO, OCS, HC3N, HNCO, CH3CN, and CH3OH J = 2–1 and J = 8–7 lines to confirm and characterize them. We applied this method to the l = 10°–20° portion of the FUGIN data and identified 22 “HotCores” (compact sources with more than two significant detections of the hot core tracer lines, i.e., SO, OCS, HC3N, HNCO, CH3CN, or CH3OH J = 8–7 lines) and 14 “DenseClumps” (sources with more than two significant detection of C34S, CH3OH J = 2–1, or the hot core tracer lines). The identified HotCores are found to be associated with signposts of high-mass star formation such as ATLASGAL clumps, WISE H ii regions, and Class II methanol masers. Many of the FUGIN HotCores are identified with the Herschel Hi-GAL clumps with a median mass of 6.8 × 102 M⊙ and a median bolometric luminosity of 7.4 × 103 L⊙. Five of the seven HotCores with stronger CH3CN lines exhibit elevated gas temperatures of 50–100 K. These observations suggest that FUGIN HotCores are closely related to the formation of stars with medium to high mass. For those associated with ATLASGAL clumps, their bolometric luminosity to clump mass ratios are consistent with the star formation stages centered at the hot core phase. The catalog of FUGIN HotCores provides a useful starting point for further statistical studies and detailed observations of high-mass star forming regions.
We report the first high spatial resolution measurement of magnetic fields surrounding LkHα 101, part of the Auriga-California molecular cloud. The observations were taken with the POL-2 polarimeter ...on the James Clerk Maxwell Telescope within the framework of the B-fields In Star-forming Region Observations (BISTRO) survey. Observed polarization of thermal dust emission at 850 μm is found to be mostly associated with the redshifted gas component of the cloud. The magnetic field displays a relatively complex morphology. Two variants of the Davis-Chandrasekhar-Fermi method, unsharp masking and structure function, are used to calculate the strength of magnetic fields in the plane of the sky, yielding a similar result of BPOS ∼ 115 μG. The mass-to-magnetic-flux ratio in critical value units, λ ∼ 0.3, is the smallest among the values obtained for other regions surveyed by POL-2. This implies that the LkHα 101 region is subcritical, and the magnetic field is strong enough to prevent gravitational collapse. The inferred δB/B0 ∼ 0.3 implies that the large-scale component of the magnetic field dominates the turbulent one. The variation of the polarization fraction with total emission intensity can be fitted by a power law with an index of α = 0.82 ± 0.03, which lies in the range previously reported for molecular clouds. We find that the polarization fraction decreases rapidly with proximity to the only early B star (LkHα 101) in the region. Magnetic field tangling and the joint effect of grain alignment and rotational disruption by radiative torques can potentially explain such a decreasing trend.
We report 850 m dust polarization observations of a low-mass (∼12 M ) starless core in the Ophiuchus cloud, Ophiuchus C, made with the POL-2 instrument on the James Clerk Maxwell Telescope (JCMT) as ...part of the JCMT B-fields In STar-forming Region Observations survey. We detect an ordered magnetic field projected on the plane of the sky in the starless core. The magnetic field across the ∼0.1 pc core shows a predominant northeast-southwest orientation centering between ∼40° and ∼100°, indicating that the field in the core is well aligned with the magnetic field in lower-density regions of the cloud probed by near-infrared observations and also the cloud-scale magnetic field traced by Planck observations. The polarization percentage (P) decreases with increasing total intensity (I), with a power-law index of −1.03 0.05. We estimate the plane-of-sky field strength (Bpos) using modified Davis-Chandrasekhar-Fermi methods based on structure function (SF), autocorrelation function (ACF), and unsharp masking (UM) analyses. We find that the estimates from the SF, ACF, and UM methods yield strengths of 103 46 G, 136 69 G, and 213 115 G, respectively. Our calculations suggest that the Ophiuchus C core is near magnetically critical or slightly magnetically supercritical (i.e., unstable to collapse). The total magnetic energy calculated from the SF method is comparable to the turbulent energy in Ophiuchus C, while the ACF method and the UM method only set upper limits for the total magnetic energy because of large uncertainties.
We present 850 m imaging polarimetry data of the Oph-A core taken with the Submillimeter Common-User Bolometer Array-2 (SCUBA-2) and its polarimeter (POL-2) as part of our ongoing survey project, ...-fields In STar forming RegiOns (BISTRO). The polarization vectors are used to identify the orientation of the magnetic field projected on the plane of the sky at a resolution of 0.01 pc. We identify 10 subregions with distinct polarization fractions and angles in the 0.2 pc Oph-A core; some of them can be part of a coherent magnetic field structure in the Oph region. The results are consistent with previous observations of the brightest regions of Oph-A, where the degrees of polarization are at a level of a few percent, but our data reveal for the first time the magnetic field structures in the fainter regions surrounding the core where the degree of polarization is much higher (>5%). A comparison with previous near-infrared polarimetric data shows that there are several magnetic field components that are consistent at near-infrared and submillimeter wavelengths. Using the Davis-Chandrasekhar-Fermi method, we also derive magnetic field strengths in several subcore regions, which range from approximately 0.2 to 5 mG. We also find a correlation between the magnetic field orientations projected on the sky and the core centroid velocity components.
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