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Abdullah Alholle, Marie Karanian, Anna T Brini, Mark R Morris, Vinodh Kannappan, Stefania Niada, Angela Niblett, Dominique Ranchère-Vince, Daniel Pissaloux, Christophe Delfour, Aurelie Maran Gonzalez, Cristina R Antonescu, Vaiyapuri Sumathi, Franck Tirode, Farida Latif
In recent years, undifferentiated small round cell sarcoma (USRCS) have been divided into a variety of new, rare, sarcoma subtypes including the group of Ewing-like sarcoma that has the morphological appearance of Ewing sarcoma but carries CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classical EWSR1-ETS. Using high-throughput RNA-seq analyses we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by RT-PCR, long-range PCR and FISH...
March 13, 2018: Journal of Pathology
Amy E Campbell, Sean C Shadle, Sujatha Jagannathan, Jong-Won Lim, Rebecca Resnick, Rabi Tawil, Silvère M van der Maarel, Stephen J Tapscott
The DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. DUX4 is normally expressed in the cleavage-stage embryo, whereas chromatin repression prevents DUX4 expression in most somatic tissues. Failure of this repression causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression of DUX4 in skeletal muscle. In this study, we used CRISPR/Cas9 engineered chromatin immunoprecipitation (enChIP) locus-specific proteomics to characterize D4Z4-associated proteins...
March 13, 2018: ELife
K Specht, W Hartmann
Sarcomas of the Ewing family of tumors are aggressive neoplasms occurring in bone and soft tissue of mostly children and young adults. Classical Ewing sarcomas are pathognomonically characterized by fusions between a gene of the RNA-binding TET family (EWSR1 or FUS) with a gene of the ETS-transcription family (FLI1, ERG, ETV1, ETV4 or FEV). Less frequent cases designated as Ewing-like sarcomas show different genetic rearrangements between EWSR1 and non-ETS genes (NFATC2, POU5F1, SMARCA5, PATZ, ZSG, SP3). Moreover, new molecular alterations biologically unrelated to Ewing sarcomas have recently been described in the category of undifferentiated round cell sarcomas including CIC-DUX4 fusions or BCOR alterations, each carrying unique gene expression signatures...
February 26, 2018: Der Pathologe
Rabi Tawil
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of the genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline...
2018: Handbook of Clinical Neurology
Darko Bosnakovski, Sunny S K Chan, Olivia O Recht, Lynn M Hartweck, Collin J Gustafson, Laura L Athman, Dawn A Lowe, Michael Kyba
In the originally published version of this Article, an incorrect grant number, RO1 NS083549, was acknowledged. The correct grant number is RO1 AR055685. This error has now been corrected in both the PDF and HTML versions of the Article.
February 22, 2018: Nature Communications
Sarah Watson, Virginie Perrin, Delphine Guillemot, Stephanie Reynaud, Jean-Michel Coindre, Marie Karanian, Jean-Marc Guinebretière, Paul Freneaux, François Le Loarer, Megane Bouvet, Louise Galmiche-Rolland, Frédérique Larousserie, Elisabeth Longchampt, Dominique Ranchere-Vince, Gaelle Pierron, Olivier Delattre, Franck Tirode
Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% percent of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR and BCOR internal duplication) tumour groups...
February 12, 2018: Journal of Pathology
Michaela C Baldauf, Martin F Orth, Marlene Dallmayer, Aruna Marchetto, Julia S Gerke, Rebeca Alba Rubio, Merve M Kiran, Julian Musa, Maximilian M L Knott, Shunya Ohmura, Jing Li, Nusret Akpolat, Ayse N Akatli, Özlem Özen, Uta Dirksen, Wolfgang Hartmann, Enrique de Alava, Daniel Baumhoer, Giuseppina Sannino, Thomas Kirchner, Thomas G P Grünewald
Ewing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4- , BCOR-CCNB3- , EWSR1-NFATc2- , and EWSR1-ETS -translocated sarcomas are distinct entities, and revealed that ATP1A1 , BCL11B , and GLG1 constitute specific markers for Ewing sarcoma...
January 5, 2018: Oncotarget
Takako Jones, Peter L Jones
The Double homeobox 4 (DUX4) gene is an important regulator of early human development and its aberrant expression is causal for facioscapulohumeral muscular dystrophy (FSHD). The DUX4-full length (DUX4-fl) mRNA splice isoform encodes a transcriptional activator; however, DUX4 and its unique DNA binding preferences are specific to old-world primates. Regardless, the somatic cytotoxicity caused by DUX4 expression is conserved when expressed in cells and animals ranging from fly to mouse. Thus, viable animal models based on DUX4-fl expression have been difficult to generate due in large part to overt developmental toxicity of low DUX4-fl expression from leaky transgenes...
2018: PloS One
Lindsay M Wallace, Nizar Y Saad, Nettie K Pyne, Allison M Fowler, Jocelyn O Eidahl, Jacqueline S Domire, Danielle A Griffin, Adam C Herman, Zarife Sahenk, Louise R Rodino-Klapac, Scott Q Harper
RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
Elisabeth M P Steeghs, Marjolein Bakker, Alex Q Hoogkamer, Judith M Boer, Quirine J Hartman, Femke Stalpers, Gabriele Escherich, Valerie de Haas, Hester A de Groot-Kruseman, Rob Pieters, Monique L den Boer
Approximately 25% of the pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases are genetically unclassified. More thorough elucidation of the pathobiology of these genetically unclassified ('B-other') cases may identify novel treatment options. We analyzed gene expression profiles of 572 pediatric BCP-ALL cases, representing all major ALL subtypes. High expression of STAP1, an adaptor protein downstream of the B-cell receptor (BCR), was identified in BCR-ABL1-like and non-BCR-ABL1-like B-other cases...
January 12, 2018: Scientific Reports
Céline Vanderplanck, Alexandra Tassin, Eugénie Ansseau, Sébastien Charron, Armelle Wauters, Céline Lancelot, Kelly Vancutsem, Dalila Laoudj-Chenivesse, Alexandra Belayew, Frédérique Coppée
BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is associated with DNA hypomethylation at the 4q35 D4Z4 repeat array. Both the causal gene DUX4 and its homolog DUX4c are induced. DUX4c is immunodetected in every myonucleus of proliferative cells, while DUX4 is present in only 1/1000 of myonuclei where it initiates a gene deregulation cascade. FSHD primary myoblasts differentiate into either atrophic or disorganized myotubes. DUX4 expression induces atrophic myotubes and associated FSHD markers...
January 12, 2018: Skeletal Muscle
Yu-Chien Kao, Adepitan A Owosho, Yun-Shao Sung, Lei Zhang, Yumi Fujisawa, Jen-Chieh Lee, Leonard Wexler, Pedram Argani, David Swanson, Brendan C Dickson, Christopher D M Fletcher, Cristina R Antonescu
BCOR-CCNB3 sarcoma (BCS) is a recently defined genetic entity among undifferentiated round cell sarcomas, which was initially classified as and treated similarly to the Ewing sarcoma (ES) family of tumors. In contrast to ES, BCS shows consistent BCOR overexpression, and preliminary evidence suggests that these tumors share morphologic features with other tumors harboring BCOR genetic alterations, including BCOR internal tandem duplication (ITD) and BCOR-MAML3. To further investigate the pathologic features, clinical behavior, and their relationship to other round cell sarcomas, we collected 36 molecularly confirmed BCSs for a detailed histologic and immunohistochemical analysis...
October 25, 2017: American Journal of Surgical Pathology
Jessica C de Greef, Yvonne D Krom, Bianca den Hamer, Lauren Snider, Yosuke Hiramuki, Rob F P van den Akker, Kelsey Breslin, Miha Pakusch, Daniela C F Salvatori, Bram Slütter, Rabi Tawil, Marnie E Blewitt, Stephen J Tapscott, Silvère M van der Maarel
In humans, a copy of the DUX4 retrogene is located in each unit of the D4Z4 macrosatellite repeat that normally comprises 8-100 units. The D4Z4 repeat has heterochromatic features and does not express DUX4 in somatic cells. Individuals with facioscapulohumeral muscular dystrophy (FSHD) have a partial failure of somatic DUX4 repression resulting in the presence of DUX4 protein in sporadic muscle nuclei. Somatic DUX4 derepression is caused by contraction of the D4Z4 repeat to 1-10 units (FSHD1) or by heterozygous mutations in genes responsible for maintaining the D4Z4 chromatin structure in a repressive state (FSHD2)...
December 21, 2017: Human Molecular Genetics
Richard Jlf Lemmers, Patrick J van der Vliet, Judit Balog, Jelle J Goeman, Wibowo Arindrarto, Yvonne D Krom, Kirsten R Straasheijm, Rashmie D Debipersad, Gizem Özel, Janet Sowden, Lauren Snider, Karlien Mul, Sabrina Sacconi, Baziel van Engelen, Stephen J Tapscott, Rabi Tawil, Silvère M van der Maarel
Facioscapulohumeral muscular dystrophy is caused by incomplete repression of the transcription factor DUX4 in skeletal muscle as a consequence of D4Z4 macrosatellite repeat contraction in chromosome 4q35 (FSHD1) or variants in genes encoding D4Z4 chromatin repressors (FSHD2). A clinical hallmark of FSHD is variability in onset and progression suggesting the presence of disease modifiers. A well-known cis modifier is the polymorphic DUX4 polyadenylation signal (PAS) that defines FSHD permissive alleles: D4Z4 chromatin relaxation on non-permissive alleles which lack the DUX4-PAS cannot cause disease in the absence of stable DUX4 mRNA...
January 2018: European Journal of Human Genetics: EJHG
Kenneth T E Chang, Angela Goytain, Tracy Tucker, Aly Karsan, Cheng-Han Lee, Torsten O Nielsen, Tony L Ng
The NanoString nCounter assay is a high-throughput hybridization technique using target-specific probes that can be customized to test for numerous fusion transcripts in a single assay using RNA from formalin-fixed, paraffin-embedded material. We designed a NanoString assay targeting 174 unique fusion junctions in 25 sarcoma types. The study cohort comprised 212 cases, 96 of which showed fusion gene expression by the NanoString assay, including all 20 Ewing sarcomas, 11 synovial sarcomas, and 5 myxoid liposarcomas tested...
November 17, 2017: Journal of Molecular Diagnostics: JMD
Satomi Mitsuhashi, So Nakagawa, Mahoko Takahashi Ueda, Tadashi Imanishi, Martin C Frith, Hiroaki Mitsuhashi
Subtelomeric macrosatellite repeats are difficult to sequence using conventional sequencing methods owing to the high similarity among repeat units and high GC content. Sequencing these repetitive regions is challenging, even with recent improvements in sequencing technologies. Among these repeats, a haplotype carrying a particular sequence and shortening of the D4Z4 array on human chromosome 4q35 causes one of the most prevalent forms of muscular dystrophy with autosomal-dominant inheritance, facioscapulohumeral muscular dystrophy (FSHD)...
November 1, 2017: Scientific Reports
Daisuke Tomizawa
Both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are common malignant diseases in adolescents and young adults (AYAs). Recent advances in genomic studies have helped us understand the biological nature of acute leukemia in AYAs; higher frequency of Ph-like ALL and rearrangements in DUX4, ERG, MEF2D, and ZNF384 genes in AYAs with ALL and higher frequency of FLT3-ITD, NPM1, IDH1/2, DNMT3A, ASXL1, TET2, and CEBPA mutations in AYAs with AML than that in children. The pediatric-inspired regimen has become a standard treatment approach for AYAs with ALL, but optimal treatment strategy for AYAs with AML is not yet established to date...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Darko Bosnakovski, Erik A Toso, Lynn M Hartweck, Alessandro Magli, Heather A Lee, Eliza R Thompson, Abhijit Dandapat, Rita C R Perlingeiro, Michael Kyba
Facioscapulohumeral muscular dystrophy (FSHD) is caused by inappropriate expression of the double homeodomain protein DUX4. DUX4 has bimodal effects, inhibiting myogenic differentiation and blocking MyoD at low levels of expression, and killing myoblasts at high levels. Pax3 and Pax7, which contain related homeodomains, antagonize the cell death phenotype of DUX4 in C2C12 cells, suggesting some type of competitive interaction. Here, we show that the effects of DUX4 on differentiation and MyoD expression require the homeodomains but do not require the C-terminal activation domain of DUX4...
November 1, 2017: Journal of Cell Science
Darko Bosnakovski, Sunny S K Chan, Olivia O Recht, Lynn M Hartweck, Collin J Gustafson, Laura L Athman, Dawn A Lowe, Michael Kyba
Facioscapulohumeral muscular dystrophy is a slowly progressive but devastating myopathy caused by loss of repression of the transcription factor DUX4; however, DUX4 expression is very low, and protein has not been detected directly in patient biopsies. Efforts to model DUX4 myopathy in mice have foundered either in being too severe, or in lacking muscle phenotypes. Here we show that the endogenous facioscapulohumeral muscular dystrophy-specific DUX4 polyadenylation signal is surprisingly inefficient, and use this finding to develop an facioscapulohumeral muscular dystrophy mouse model with muscle-specific doxycycline-regulated DUX4 expression...
September 15, 2017: Nature Communications
Alec M DeSimone, Anna Pakula, Angela Lek, Charles P Emerson
Facioscapulohumeral Muscular Dystrophy is a common form of muscular dystrophy that presents clinically with progressive weakness of the facial, scapular, and humeral muscles, with later involvement of the trunk and lower extremities. While typically inherited as autosomal dominant, facioscapulohumeral muscular dystrophy (FSHD) has a complex genetic and epigenetic etiology that has only recently been well described. The most prevalent form of the disease, FSHD1, is associated with the contraction of the D4Z4 microsatellite repeat array located on a permissive 4qA chromosome...
September 12, 2017: Comprehensive Physiology
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