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https://www.readbyqxmd.com/read/29330417/high-stap1-expression-in-dux4-rearranged-cases-is-not-suitable-as-therapeutic-target-in-pediatric-b-cell-precursor-acute-lymphoblastic-leukemia
#1
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
https://www.readbyqxmd.com/read/29329560/overexpression-of-the-double-homeodomain-protein-dux4c-interferes-with-myofibrillogenesis-and-induces-clustering-of-myonuclei
#2
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
https://www.readbyqxmd.com/read/29300189/bcor-ccnb3-fusion-positive-sarcomas-a-clinicopathologic-and-molecular-analysis-of-36-cases-with-comparison-to-morphologic-spectrum-and-clinical-behavior-of-other-round-cell-sarcomas
#3
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
https://www.readbyqxmd.com/read/29281018/smchd1-haploinsufficiency-exacerbates-the-phenotype-of-a-transgenic-fshd1-mouse-model
#4
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
https://www.readbyqxmd.com/read/29162933/deep-characterization-of-a-common-d4z4-variant-identifies-biallelic-dux4-expression-as-a-modifier-for-disease-penetrance-in-fshd2
#5
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...
November 21, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29104083/development-and-evaluation-of-a-pan-sarcoma-fusion-gene-detection-assay-using-the-nanostring-ncounter-platform
#6
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
https://www.readbyqxmd.com/read/29093467/nanopore-based-single-molecule-sequencing-of-the-d4z4-array-responsible-for-facioscapulohumeral-muscular-dystrophy
#7
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
https://www.readbyqxmd.com/read/28978861/acute-leukemia-in-adolescents-and-young-adults
#8
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
https://www.readbyqxmd.com/read/28935672/the-dux4-homeodomains-mediate-inhibition-of-myogenesis-and-are-functionally-exchangeable-with-the-pax7-homeodomain
#9
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 effects on differentiation and MyoD expression require the homeodomains but do not require the C-terminal activation domain of DUX4...
September 21, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28916757/muscle-pathology-from-stochastic-low-level-dux4-expression-in-an-fshd-mouse-model
#10
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
https://www.readbyqxmd.com/read/28915324/facioscapulohumeral-muscular-dystrophy
#11
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
https://www.readbyqxmd.com/read/28883266/acute-lymphoblastic-leukemia-of-adolescents-and-young-adults-from-the-viewpoint-of-physicians
#12
Takahiko Yasuda, Fumihiko Hayakawa
Fusion genes found in cases of acute lymphoblastic leukemia (ALL) are reported to be associated with age, such as MLL rearrangements in neonates and BCR-ABL1 in adults. However, the pathogenesis of ALL in adolescents and young adults (AYA) remains largely unknown. To investigate the potential role of fusion genes, we performed RNA-sequencing on 73 BCR-ABL1-negative ALL patients who were all AYA. Interestingly, DUX4-IGH was the most frequent fusion gene detected in B-ALL (18.5%) and was preferentially detected in the AYA generation...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28870238/bet-bromodomain-inhibitors-and-agonists-of-the-beta-2-adrenergic-receptor-identified-in-screens-for-compounds-that-inhibit-dux4-expression-in-fshd-muscle-cells
#13
Amy E Campbell, Jonathan Oliva, Matthew P Yates, Jun Wen Zhong, Sean C Shadle, Lauren Snider, Nikita Singh, Shannon Tai, Yosuke Hiramuki, Rabi Tawil, Silvère M van der Maarel, Stephen J Tapscott, Francis M Sverdrup
BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD. METHODS: We screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures...
September 4, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28806978/transcriptome-sequencing-in-pediatric-acute-lymphoblastic-leukemia-identifies-fusion-genes-associated-with-distinct-dna-methylation-profiles
#14
Yanara Marincevic-Zuniga, Johan Dahlberg, Sara Nilsson, Amanda Raine, Sara Nystedt, Carl Mårten Lindqvist, Eva C Berglund, Jonas Abrahamsson, Lucia Cavelier, Erik Forestier, Mats Heyman, Gudmar Lönnerholm, Jessica Nordlund, Ann-Christine Syvänen
BACKGROUND: Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. METHODS: We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes...
August 14, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28759137/soft-tissue-sarcomas-from-a-morphological-to-a-molecular-biological-approach
#15
REVIEW
Yoshinao Oda, Hidetaka Yamamoto, Kenichi Kohashi, Yuichi Yamada, Kunio Iura, Takeaki Ishii, Akira Maekawa, Hirofumi Bekki
Recently developed molecular genetic techniques have led to the elucidation of tumor-specific genomic alterations and thereby the reclassification of tumor entities of soft tissue sarcoma. A solitary fibrous tumor-mimicking tumor with the AHRR-NCOA2 gene has been isolated as angiofibroma of soft tissue. As for small round cell sarcomas, novel fusion genes such as CIC-DUX4 and BCOR-CCNB3 have been identified in these tumor groups. SMARCB1/INI1 deficient tumors with round cell morphology are also expected to be reclassified in three types, based on the combination of their morphology and genotype...
September 2017: Pathology International
https://www.readbyqxmd.com/read/28754837/p53-independent-dux4-pathology-in-cell-and-animal-models-of-facioscapulohumeral-muscular-dystrophy
#16
Darko Bosnakovski, Micah D Gearhart, Erik A Toso, Olivia O Recht, Anja Cucak, Abhinav K Jain, Michelle C Barton, Michael Kyba
Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant myopathy caused by mutations that disrupt repression of the normally silent DUX4 gene, which encodes a transcription factor that has been shown to interfere with myogenesis when misexpressed at very low levels in myoblasts and to cause cell death when overexpressed at high levels. A previous report using adeno-associated virus to deliver high levels of DUX4 to mouse skeletal muscle demonstrated severe pathology that was suppressed on a p53-knockout background, implying that DUX4 acted through the p53 pathway...
October 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28690764/are-antioxidants-a-potential-therapy-for-fshd-a-review-of-the-literature
#17
REVIEW
Adam Philip Denny, Alison Kay Heather
Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy affecting approximately 1 in 7500 individuals worldwide. It is a progressive disease characterised by skeletal muscle weakness and wasting. A genetic mutation on the 4q35 chromosome results in the expression of the double homeobox 4 gene (DUX4) which drives oxidative stress, inflammation, toxicity, and atrophy within the skeletal muscle. FSHD is characterised by oxidative stress, and there is currently no cure and a lack of therapies for the disease...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28680140/generation-of-novel-patient-derived-cic-dux4-sarcoma-xenografts-and-cell-lines
#18
Rieko Oyama, Mami Takahashi, Akihiko Yoshida, Marimu Sakumoto, Yoko Takai, Fusako Kito, Kumiko Shiozawa, Zhiwei Qiao, Yasuhito Arai, Tatsuhiro Shibata, Yoshihiro Araki, Makoto Endo, Akira Kawai, Tadashi Kondo
CIC-DUX4 sarcoma (CDS) is a group of rare, mesenchymal, small round cell tumours that harbour the unique CIC-DUX4 translocation, which causes aberrant gene expression. CDS exhibits an aggressive course and poor clinical outcome, thus novel therapeutic approaches are needed for CDS treatment. Although patient-derived cancer models are an essential modality to develop novel therapies, none currently exist for CDS. Thus, the present study successfully established CDS patient-derived xenografts and subsequently generated two CDS cell lines from the grafted tumours...
July 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28645808/primary-undifferentiated-small-round-cell-sarcoma-of-the-deep-abdominal-wall-with-a-novel-variant-of-t-10-19-cic-dux4-gene-fusion
#19
Yoshitane Tsukamoto, Hiroyuki Futani, Shinichi Yoshiya, Takahiro Watanabe, Takako Kihara, Shohei Matsuo, Seiichi Hirota
We experienced a 38-year-old Japanese male with t(10;19) CIC-DUX4 -positive undifferentiated small round cell sarcoma in the deep abdominal wall. Three months before his first visit to our hospital, he noticed a mass in his right abdominal wall. Computed tomography on admission revealed a solid abdominal tumor 70×53mm in size and multiple small tumors in both lungs. The biopsy of the abdominal tumor revealed undifferentiated small round cell sarcoma, suggestive of Ewing sarcoma. Under the clinical diagnosis of Ewing-like sarcoma of the abdominal wall with multiple lung metastases, several cycles of ICE (ifosfamide, carboplatin and etoposide) therapy were performed...
October 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/28643791/ewsr1-fusion-proteins-mediate-pax7-expression-in-ewing-sarcoma
#20
Gregory W Charville, Wei-Lien Wang, Davis R Ingram, Angshumoy Roy, Dafydd Thomas, Rajiv M Patel, Jason L Hornick, Matt van de Rijn, Alexander J Lazar
PAX7 is a paired-box transcription factor that is required for the developmental specification of adult skeletal muscle progenitors in mice. We previously demonstrated PAX7 expression as a marker of skeletal muscle differentiation in rhabdomyosarcoma. Here, using analyses of published whole-genome gene expression microarray data, we identify PAX7 as a gene with significantly increased expression in Ewing sarcoma in comparison to CIC-DUX4 round cell sarcoma. Analysis of PAX7 in a large cohort of 103 Ewing sarcoma cases by immunohistochemistry revealed expression in 99...
September 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
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