ALBERT

Description: Shallow slab devolatilization is not only witnessed through fluid expulsion at accretionary prisms, but is also evidenced by active serpentinite seamounts in the shallow fore-arc region of the Mariana convergent margin. Ocean Drilling Program (ODP) Leg 195 recovered serpentinized peridotites that present a unique opportunity to study the products of shallow level exchanges between the upper mantle and slab-derived fluids. Similar to samples recovered during ODP Leg 125, the protoliths of these fore-arc serpentinized peridotites are mantle harzburgites that have suffered large volume melt extraction (up to 25%) prior to interactions with fluids released from the downgoing Pacific Plate. Samples recovered from both ODP legs 125 and 195 show U-shaped rare earth element (REE) patterns and very low REE abundances (0.001–0.1 chondrites). Relative to global depleted mantle values these rocks typically have 1–2 orders of magnitude lower high field strength elements, REE, Th, and U contents. Interestingly, all fore-arc rocks thus far examined show extreme enrichments of fluid mobile elements (FME: B, As, Cs, Sb, Li). Because the elemental and B, Li, and Sr isotope systematics in these fore-arc serpentinites point to nonseawater-related processes, studies of elemental excesses and anomalous isotopic signatures allow assessment of how much of the subducted inventory is lost during the initial subduction process between 10 and 40 km. On the basis of similar but substantial enrichments of FME in the Mariana fore-arc samples recovered at ODP legs 125 and 195, we report large slab inventory depletions of B ( 75%), Cs ( 25%), As ( 15%), Li ( 15%), and Sb ( 8%); surprisingly low (generally less than 2%) depletions of Rb, Ba, Pb, U, Sr; and no depletions in REE and the high field strength elements (HFSE). Such slab-metasomatized mantle wedge materials may be dragged to depths of arc magma generation, as proposed by Tatsumi (1986) and Straub and Layne (2002) and thus represent an unexplored class of mantle material, different in its origins, physical properties and geochemical fingerprint from mantle rocks traditionally used in modeling a wide range of subduction zone processes.

Description: Published

Description: B09205

Description: 2.3. TTC - Laboratori di chimica e fisica delle rocce

Description: JCR Journal

Description: reserved

Description: Recent examinations of the chemical fluxes through convergent plate margins suggest the existence of significant mass imbalances for many key species: only 20–30% of the to-the-trench inventory of large-ion lithophile elements (LILE) can be accounted for by the magmatic outputs of volcanic arcs. Active serpentinite mud volcanism in the shallow forearc region of the Mariana convergent margin presents a unique opportunity to study a new outflux: the products of shallow-level exchanges between the upper mantle and slab-derived fluids. ODP Leg 125 recovered serpentinized harzburgites and dunites from three sites on the crests and flanks of the active Conical Seamount. These serpentinites have U-shaped rare earth element (REE) patterns, resembling those of boninites. U, Th, and the high field strength elements (HFSE) are highly depleted and vary in concentration by up to 2 orders of magnitude. The low U contents and positive Eu anomalies indicate that fluids from the subducting Pacific slab were probably reducing in nature. On the basis of substantial enrichments of fluid-mobile elements in serpentinized peridotites, we calculated very large slab inventory depletions of B (79%), Cs (32%), Li (18%), As (17%), and Sb (12%). Such highly enriched serpentinized peridotites dragged down to depths of arc magma generation may represent an unexplored reservoir that could help balance the input-output deficit of these elements as observed by Plank and Langmuir (1993, 1998) and others. Surprisingly, many species thought to be mobile in fluids, such as U, Ba, Rb, and to a lesser extent Sr and Pb, are not enriched in the rocks relative to the depleted mantle peridotites, and we estimate that only 1–2% of these elements leave the subducting slabs at depths of 10 to 40 km. Enrichments of these elements in volcanic front and behind-the-front arc lavas point to changes in slab fluid composition at greater depths.

Description: Published

Description: 1-24

Description: partially_open

Description: Although recent data suggests that osteoblasts play a key role within the hematopoietic stem cell (HSC) niche, the mechanisms underpinning this remain to be fully defined. The studies described herein examine the role in hematopoiesis of Osteopontin (Opn), a multidomain, phosphorylated glycoprotein, synthesized by osteoblasts, with well-described roles in cell adhesion, inflammatory responses, angiogenesis, and tumor metastasis. We demonstrate a previously unrecognized critical role for Opn in regulation of the physical location and proliferation of HSCs. Within marrow, Opn expression is restricted to the endosteal bone surface and contributes to HSC transmarrow migration toward the endosteal region, as demonstrated by the markedly aberrant distribution of HSCs in Opn–/– mice after transplantation. Primitive hematopoietic cells demonstrate specific adhesion to Opn in vitro via β1 integrin. Furthermore, exogenous Opn potently suppresses the proliferation of primitive HPCs in vitro, the physiologic relevance of which is demonstrated by the markedly enhanced cycling of HSC in Opn–/– mice. These data therefore provide strong evidence that Opn is an important component of the HSC niche which participates in HSC location and as a physiologic-negative regulator of HSC proliferation.

Description: Abstract 1279 Poster Board I-301 The MLL (mixed-lineage leukemia) gene at chromosome band 11q23 is rearranged frequently in AML and ALL, and associated with poor prognosis. The consequence of these translocations is the formation of a chimeric oncogenic transcription factor that specifies a unique expression signature distinct from other subtypes of acute leukemia. However, it is poorly understood, which changes in gene expression in leukemic cells are under the direct control of MLL fusion proteins (fusion), nor is it clear what is the potential overlap between MLL wild type (WT) and fusion target genes. In the present study, we used genome-wide location analysis to determine the genomic loci that are specifically bound by MLL fusion proteins. Combining the binding analysis with expression profiling, we further defined the subset of MLL fusion-bound genes whose expression is regulated by the presence of MLL fusion proteins. Using ChIP-chip (Chromatin Immunoprecipitation coupled with micro-array), we determined the MLL-bound regions in 5 myeloid leukemic cell lines using a custom array containing the entire genomic region of 200 genes previously found to have altered expression in MLL-rearranged leukemias. Examination of these 200 genomic loci revealed a largely overlapping set of genes bound by MLL (wild type and/or fusion proteins) in WT/WT (U937: 110 genes, HL60: 79 genes) and WT/Fusion cells (MV4;11: 62 genes, THP-1: 89 genes). Surprisingly, the MLL-bound genes in fusion/fusion (ML-2) cells (25 genes) are a small subset of that found in each of the other 4 cell lines, despite comparable levels of detected MLL binding signal across all lines examined. These data suggest that the MLL fusion protein is likely only localized to a limited portion of genomic loci occupied by the MLL wild type protein. To test this hypothesis in a more systematic way, we examined an inducible MLL-ENL–ER transformed cell line (Slany et al, MCB 2004), which grow as myeloblastic cells in the presence of MLL-ENL, and differentiate into neutrophils upon inactivation of the fusion protein. As MLL-ENL promotes histone H3 lysine 79 (H3K79) methylation, we determined both MLL binding and H3K79 methylation using a genome-wide location analysis. We anticipated that MLL-fusion bound genomic regions would exhibit a significant drop in either MLL and/or K79 signal upon inactivation of MLL-ENL. Unexpectedly, among thousands of genes that are bound by MLL, only 10% of them (222 genes) showed a pattern of binding increase between MLL-ENL induced and un-induced conditions. To explore the impact of MLL fusion protein on gene activation, we performed whole genome expression profiling in the presence or absence of MLL-ENL. Increased levels of either MLL binding or H3K79 methylation are significantly associated with differential gene expression. Among 222 MLL fusion target genes, 12 of them are differentially up-regulated in the presence of MLL-ENL, indicating that a large fraction of MLL fusion bound genes do not exhibit significant changes in mRNA expression. The identified 12 genes include key regulators in cellular differentiation and cell cycle regulation, as well as Meis1, Hoxa9 which are known to be essential for the development of MLL leukemia. To explore the apparent discrepancy between the massive expression changes in MLL rearranged leukemia and the small number of direct fusion target genes we identified, we tested the hypothesis that a significant portion of the MLL fusion protein expression signature was derived from its direct fusion target genes Meis1 and Hoxa9. Using publicly available data, we compared the MLL leukemia associated expression profile with the set of genes that were down-regulated upon knock-down of Meis1 and Hoxa9. We found significant enrichment of Hoxa9/Meis1 downstream targets in the expression profile defined by MLL fusion proteins. Altogether, our data suggest that MLL fusion proteins are likely to contribute to the development of acute leukemia through direct activation of a very small set of genes. The results have important implications in understanding the mechanisms of target gene specificity involving oncogenic transcription factors. Disclosures No relevant conflicts of interest to declare.

Description: Key steps in hematopoiesis and the expression of genes encoding hemoglobin subunits are critically dependent upon specific members of the GATA factor family of transcription factors. Our recent efforts have focused on elucidating how GATA factors select functional sites in chromatin and how they function combinatorially with additional regulatory factors. GATA motifs are often arranged in close proximity to E-boxes, and such composite elements commonly mediate GATA factor- and Scl/TAL1-dependent transcriptional responses. Only a small fraction of these composite elements in chromatin are occupied by GATA factors and Scl/TAL1, and a specific epigenetic signature distinguishes occupied versus unoccupied elements genome-wide. In the context of hemoglobin synthesis, we are using genetic and molecular approaches to dissect the multistep mechanism underlying the control of β-globin transcription. GATA-1-containing complexes assemble at the β-globin Locus Control Region (LCR) prior to the murine adult βmajor promoter. Though the LCR physically interacts with the βmajor promoter, this interaction is not required for the binding of several trans-acting factors to the LCR or the promoter. A hypomorphic mutation of the chromatin remodeler BRG1 limits the extent to which RNA Polymerase II (Pol II) is recruited to the promoter and also abrogates the LCR-promoter interaction. Whereas looping is not required for assembly of the full complement of promoter complex components, looping is linked to the establishment of maximal levels of Pol II at the promoter. Collectively, these results provide insights into the relationship between, and importance of, individual steps in the multi-step activation mechanism. I will discuss progress on unraveling mechanisms underlying GATA-1-mediated activation of the adult β-like globin genes as well as fundamental aspects of GATA factor function, which have broad relevance in diverse systems. promoter. Though the LCR physically interacts with the β promoter, this interaction is not required for the binding of several -acting factors to the LCR or the promoter. A hypomorphic mutation of the chromatin remodeler BRG1 limits the extent to which RNA Polymerase II (Pol II) is recruited to the promoter and also abrogates the LCR-promoter interaction. Whereas looping is not required for assembly of the full complement of promoter complex components, looping is linked to the establishment of maximal levels of Pol II at the promoter. Collectively, these results provide insights into the relationship between, and importance of, individual steps in the multi-step activation mechanism. I will discuss progress on unraveling mechanisms underlying GATA-1-mediated activation of the adult β-like globin genes as well as fundamental aspects of GATA factor function, which have broad relevance in diverse systems.