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Ulrich G. Steidl

Eric M Pietras, Cristina Mirantes-Barbeito, Sarah Fong, Dirk Loeffler, Larisa V Kovtonyuk, SiYi Zhang, Ranjani Lakshminarasimhan, Chih Peng Chin, José-Marc Techner, Britta Will, Claus Nerlov, Ulrich Steidl, Markus G Manz, Timm Schroeder, Emmanuelle Passegué
Haematopoietic stem cells (HSCs) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory 'emergency' signal, directly accelerates cell division and myeloid differentiation of HSCs through precocious activation of a PU.1-dependent gene program...
June 2016: Nature Cell Biology
Kathrin Philipp-Abbrederis, Ken Herrmann, Stefan Knop, Margret Schottelius, Matthias Eiber, Katharina Lückerath, Elke Pietschmann, Stefan Habringer, Carlos Gerngroß, Katharina Franke, Martina Rudelius, Andreas Schirbel, Constantin Lapa, Kristina Schwamborn, Sabine Steidle, Elena Hartmann, Andreas Rosenwald, Saskia Kropf, Ambros J Beer, Christian Peschel, Hermann Einsele, Andreas K Buck, Markus Schwaiger, Katharina Götze, Hans-Jürgen Wester, Ulrich Keller
CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination and poor prognosis. We evaluated the novel CXCR4 probe [(68)Ga]Pentixafor for in vivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [(68)Ga]Pentixafor PET provided images with excellent specificity and contrast...
April 2015: EMBO Molecular Medicine
Julia Fröbel, Ron-Patrick Cadeddu, Sonja Hartwig, Ingmar Bruns, Christian M Wilk, Andrea Kündgen, Johannes C Fischer, Thomas Schroeder, Ulrich G Steidl, Ulrich Germing, Stefan Lehr, Rainer Haas, Akos Czibere
Bleeding complications are a significant clinical problem in patients with myelodysplastic syndromes even at sufficient platelet counts (>50,000/μl). However, the underlying pathology of this hemorrhagic diathesis is still unknown. Here, we analyzed the platelet proteome of patients with myelodysplastic syndromes by quantitative two-dimensional difference gel electrophoresis followed by mass spectrometric protein identification. Proteins identified with lower concentrations, such as Talin-1, Vinculin, Myosin-9, Filmain-A, and Actin play critical roles in integrin αIIbβ3 signaling and thus platelet aggregation...
May 2013: Molecular & Cellular Proteomics: MCP
Michael Roth, Britta Will, Guillermo Simkin, Swathi Narayanagari, Laura Barreyro, Boris Bartholdy, Roni Tamari, Constantine S Mitsiades, Amit Verma, Ulrich Steidl
Eltrombopag (EP) is a small-molecule, nonpeptide thrombopoietin receptor (TPO-R) agonist that has been approved recently for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura. Prior studies have shown that EP stimulates megakaryopoiesis in BM cells from patients with acute myeloid leukemia and myelodysplastic syndrome, and the results also suggested that it may inhibit leukemia cell growth. In the present study, we studied the effects of EP on leukemia cell proliferation and the mechanism of its antiproliferative effects...
July 12, 2012: Blood
Christian Steidl, Sohrab P Shah, Bruce W Woolcock, Lixin Rui, Masahiro Kawahara, Pedro Farinha, Nathalie A Johnson, Yongjun Zhao, Adele Telenius, Susana Ben Neriah, Andrew McPherson, Barbara Meissner, Ujunwa C Okoye, Arjan Diepstra, Anke van den Berg, Mark Sun, Gillian Leung, Steven J Jones, Joseph M Connors, David G Huntsman, Kerry J Savage, Lisa M Rimsza, Douglas E Horsman, Louis M Staudt, Ulrich Steidl, Marco A Marra, Randy D Gascoyne
Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features. In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq)...
March 17, 2011: Nature
Karen B O'Brien, Meritxell Alberich-Jordà, Neelu Yadav, Olivier Kocher, Annalisa Diruscio, Alexander Ebralidze, Elena Levantini, Natasha J L Sng, Manoj Bhasin, Tyler Caron, Daehoon Kim, Ulrich Steidl, Gang Huang, Balázs Halmos, Scott J Rodig, Mark T Bedford, Daniel G Tenen, Susumu Kobayashi
Coactivator-associated arginine methyltransferase I (CARM1; PRMT4) regulates gene expression by multiple mechanisms including methylation of histones and coactivation of steroid receptor transcription. Mice lacking CARM1 are small, fail to breathe and die shortly after birth, demonstrating the crucial role of CARM1 in development. In adults, CARM1 is overexpressed in human grade-III breast tumors and prostate adenocarcinomas, and knockdown of CARM1 inhibits proliferation of breast and prostate cancer cell lines...
July 2010: Development
Britta Will, Tanya Siddiqi, Meritxell Alberich Jordà, Takeshi Shimamura, Katarina Luptakova, Philipp B Staber, Daniel B Costa, Ulrich Steidl, Daniel G Tenen, Susumu Kobayashi
The activating mutation JAK2 V617F plays a central role in the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2. However, the proapoptotic proteins involved in JAK2 inhibition-induced apoptosis remain unclear. In this study, we show that JAK2 inhibition-induced apoptosis correlated with up-regulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations...
April 8, 2010: Blood
Mirle Schemionek, Christian Elling, Ulrich Steidl, Nicole Bäumer, Ashley Hamilton, Tilmann Spieker, Joachim R Göthert, Martin Stehling, Amy Wagers, Claudia S Huettner, Daniel G Tenen, Lara Tickenbrock, Wolfgang E Berdel, Hubert Serve, Tessa L Holyoake, Carsten Müller-Tidow, Steffen Koschmieder
In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCR-ABL(+) Lin(-)Sca-1(+)c-kit(+) (LSK) cells. Interestingly, the phenotype is more severe when unfractionated bone marrow cells are transplanted, yet neither progenitor cells (Lin(-)Sca-1(-)c-kit(+)), nor mature granulocytes (CD11b(+)Gr-1(+)), nor potential stem cell niche cells (CD45(-)Ter119(-)) are able to transmit the disease or alter the phenotype. The phenotype is largely independent of BCR-ABL priming before transplantation...
April 22, 2010: Blood
Alexander K Ebralidze, Florence C Guibal, Ulrich Steidl, Pu Zhang, Sanghoon Lee, Boris Bartholdy, Meritxell Alberich Jorda, Victoria Petkova, Frank Rosenbauer, Gang Huang, Tajhal Dayaram, Johanna Klupp, Karen B O'Brien, Britta Will, Maarten Hoogenkamp, Katherine L B Borden, Constanze Bonifer, Daniel G Tenen
The transcription factor PU.1 is an important regulator of hematopoiesis; precise expression levels are critical for normal hematopoietic development and suppression of leukemia. We show here that noncoding antisense RNAs are important modulators of proper dosages of PU.1. Antisense and sense RNAs are regulated by shared evolutionarily conserved cis-regulatory elements, and we can show that antisense RNAs inhibit PU.1 expression by modulating mRNA translation. We propose that such antisense RNAs will likely be important in the regulation of many genes and may be the reason for the large number of overlapping complementary transcripts with so far unknown function...
August 1, 2008: Genes & Development
Ingmar Bruns, Ulrich Steidl, Johannes C Fischer, Akos Czibere, Guido Kobbe, Sascha Raschke, Raminder Singh, Roland Fenk, Michael Rosskopf, Sabrina Pechtel, Arndt von Haeseler, Peter Wernet, Daniel G Tenen, Rainer Haas, Ralf Kronenwett
BACKGROUND: Pegylated granulocyte colony-stimulating factor (G-CSF) has recently been introduced as a new compound for mobilization of CD34(+) hematopoietic stem and progenitor cells. In this study, we compared the molecular and functional characteristics of CD34(+) cells mobilized by pegylated G-CSF with those mobilized by unconjugated G-CSF. DESIGN AND METHODS: Gene expression of immunomagnetically enriched CD34(+) cells from leukapheresis products of patients who were given pegylated-G-CSF or unconjugated G-CSF was analyzed using Affymetrix HG Focus microarrays and quantitative reverse transcriptase polymerase chain reaction...
March 2008: Haematologica
Ulrich Steidl, Christian Steidl, Alexander Ebralidze, Björn Chapuy, Hye-Jung Han, Britta Will, Frank Rosenbauer, Annegret Becker, Katharina Wagner, Steffen Koschmieder, Susumu Kobayashi, Daniel B Costa, Thomas Schulz, Karen B O'Brien, Roel G W Verhaak, Ruud Delwel, Detlef Haase, Lorenz Trümper, Jürgen Krauter, Terumi Kohwi-Shigematsu, Frank Griesinger, Daniel G Tenen
Targeted disruption of a highly conserved distal enhancer reduces expression of the PU.1 transcription factor by 80% and leads to acute myeloid leukemia (AML) with frequent cytogenetic aberrations in mice. Here we identify a SNP within this element in humans that is more frequent in AML with a complex karyotype, leads to decreased enhancer activity, and reduces PU.1 expression in myeloid progenitors in a development-dependent manner. This SNP inhibits binding of the chromatin-remodeling transcriptional regulator special AT-rich sequence binding protein 1 (SATB1)...
September 2007: Journal of Clinical Investigation
Susumu Kobayashi, Takeshi Shimamura, Stefano Monti, Ulrich Steidl, Christopher J Hetherington, April M Lowell, Todd Golub, Matthew Meyerson, Daniel G Tenen, Geoffrey I Shapiro, Balázs Halmos
Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain determine responsiveness to EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer (NSCLC). The modulation of transcriptional pathways by mutant EGFR signaling is not fully understood. Previously, we and others identified a single base pair change leading to a threonine to methionine (T790M) amino acid alteration in the ATP-binding pocket of the EGFR as a common mechanism of acquired resistance...
December 1, 2006: Cancer Research
Ulrich Steidl, Frank Rosenbauer, Roel G W Verhaak, Xuesong Gu, Alexander Ebralidze, Hasan H Otu, Steffen Klippel, Christian Steidl, Ingmar Bruns, Daniel B Costa, Katharina Wagner, Manuel Aivado, Guido Kobbe, Peter J M Valk, Emmanuelle Passegué, Towia A Libermann, Ruud Delwel, Daniel G Tenen
Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. Restoration of c-Jun expression in preleukemic cells rescued the PU.1 knockdown-initiated myelomonocytic differentiation block...
November 2006: Nature Genetics
Roland Fenk, Nadine Hieronimus, Ulrich Steidl, Ingmar Bruns, Thorsten Graef, Fabian Zohren, Leilani Ruf, Rainer Haas, Guido Kobbe
OBJECTIVE: Pegfilgrastim has shown to decrease the duration of severe neutropenia after conventional chemotherapy, but its use after high-dose chemotherapy and autologous blood stem cell transplantation has not been established yet. Therefore we studied the efficacy and the pharmacokinetic profile of pegfilgrastim in patients with multiple myeloma undergoing high-dose chemotherapy. METHOD: In total, 21 patients received a single subcutaneous injection of 6 mg pegfilgrastim on day +1 after transplantation and pegfilgrastim plasma levels were measured daily by enzyme-linked immunosorbent assay...
October 2006: Experimental Hematology
Silke Schüle, Stefanie Steidl, Sylvia Panitz, Cheick Coulibaly, Ulrich Kalinke, Klaus Cichutek, Matthias Schweizer
The coreceptor usage of HIV-1 envelope proteins (Env) is mainly dependent on a defined variable region within the V3-loop of Env. Thus, retroviral vectors derived from murine leukemia virus (MLV), which have been pseudotyped with HIV-1 envelope proteins holding different V3-loops, enable selective gene delivery into either CXCR4 or CCR5 positive cultured cells. Here, we tested the distribution of CD4/CCR5-tropic [MLV(HIV)]-pseudotype vectors in transgenic mice expressing CD4 and either CXCR4 or CCR5 of human origin...
July 20, 2006: Virology
Ingmar Bruns, Ulrich Steidl, Ralf Kronenwett, Roland Fenk, Thorsten Graef, Ulrich-Peter Rohr, Frank Neumann, Johannes Fischer, Christof Scheid, Kai Hübel, Rainer Haas, Guido Kobbe
BACKGROUND: Current regimens for peripheral blood progenitor cell (PBPC) mobilization in patients with multiple myeloma are based on daily subcutaneous injections of granulocyte-colony-stimulating factor (G-CSF) starting shortly after cytotoxic therapy. Recently a polyethylene glycol-conjugated G-CSF (pegfilgrastim) was introduced that has a substantially longer t(1/2) than the original formula. STUDY DESIGN AND METHODS: The use of pegfilgrastim was examined at two dose levels for PBPC mobilization in patients with Stage II or III multiple myeloma...
February 2006: Transfusion
Frank Rosenbauer, Bronwyn M Owens, Li Yu, Joseph R Tumang, Ulrich Steidl, Jeffery L Kutok, Linda K Clayton, Katharina Wagner, Marina Scheller, Hiromi Iwasaki, Chunhui Liu, Björn Hackanson, Koichi Akashi, Achim Leutz, Thomas L Rothstein, Christoph Plass, Daniel G Tenen
Tight regulation of transcription factors, such as PU.1, is crucial for generation of all hematopoietic lineages. We previously reported that mice with a deletion of an upstream regulatory element (URE) of the gene encoding PU.1 (Sfpi1) developed acute myeloid leukemia. Here we show that the URE has an essential role in orchestrating the dynamic PU.1 expression pattern required for lymphoid development and tumor suppression. URE deletion ablated B2 cells but stimulated growth of B1 cells in mice. The URE was a PU...
January 2006: Nature Genetics
Steffen Koschmieder, Frank Rosenbauer, Ulrich Steidl, Bronwyn M Owens, Daniel G Tenen
Differentiation of hematopoietic stem and progenitor cells is under strict control of a regulatory network orchestrated by lineage-specific transcription factors. A block in normal differentiation is a major contributing factor in the development of solid tumors and leukemias. Cells from patients with acute myeloid leukemia (AML) frequently harbor mutated or dysregulated transcription factor genes, suggesting their involvement in leukemogenesis. As a consequence, these alterations diminish the pool of available molecules of a small number of critical transcription factors, such as CCAAT enhancer binding proteins, PU...
June 2005: International Journal of Hematology
Frank Rosenbauer, Steffen Koschmieder, Ulrich Steidl, Daniel G Tenen
Increasing evidence suggests that leukemias are sustained by leukemic stem cells. However, the molecular pathways underlying the transformation of normal cells into leukemic stem cells are still poorly understood. The involvement of a small group of key transcription factors into this process was suggested by their frequent mutation or down-regulation in patients with acute myeloid leukemia (AML). Recent findings in mice with hypomorphic transcription-factor genes demonstrated that leukemic stem-cell formation in AML could directly be caused by reduced transcription-factor activity beyond a critical threshold...
September 1, 2005: Blood
Ralf Kronenwett, Ulf Butterweck, Ulrich Steidl, Slawomir Kliszewski, Frank Neumann, Simone Bork, Elena Diaz Blanco, Nicole Roes, Thorsten Gräf, Benedikt Brors, Roland Eils, Christian Maercker, Guido Kobbe, Norbert Gattermann, Rainer Haas
Chronic myelogenous leukemia (CML) is a malignant disorder of the hematopoietic stem cell characterized by the BCR-ABL oncogene. We examined gene expression profiles of highly enriched CD34(+) hematopoietic stem and progenitor cells from patients with CML in chronic phase using cDNA arrays covering 1.185 genes. Comparing CML CD34(+) cells with normal CD34(+) cells, we found 158 genes which were significantly differentially expressed. Gene expression patterns reflected BCR-ABL-induced functional alterations such as increased cell-cycle and proteasome activity...
August 11, 2005: Oncogene
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