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1. The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis

Author

Jayne E. Murray, Emanuele Valli, Giorgio Milazzo, Chelsea Mayoh, Andrew J. Gifford, Jamie I. Fletcher, Chengyuan Xue, Nisitha Jayatilleke, Firoozeh Salehzadeh, Laura D. Gamble, Jourdin R. C. Rouaen, Daniel R. Carter, Helen Forgham, Eric O. Sekyere, Joanna Keating, Georgina Eden, Sophie Allan, Stephanie Alfred, Frances K. Kusuma, Ashleigh Clark, Hannah Webber, Amanda J. Russell, Antoine de Weck, Benjamin T. Kile, Martina Santulli, Piergiuseppe De Rosa, Emmy D. G. Fleuren, Weiman Gao, Lorna Wilkinson-White, Jason K. K. Low, Joel P. Mackay, Glenn M. Marshall, Douglas J. Hilton, Federico M. Giorgi, Jan Koster, Giovanni Perini, Michelle Haber, and Murray D. Norris

Subjects
Science
Abstract

Abstract MYCN oncogene amplification is frequently observed in aggressive childhood neuroblastoma. Using an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice, we identify a single germline point mutation in the transcriptional corepressor Runx1t1, which abolishes MYCN-driven tumorigenesis. This loss-of-function mutation disrupts a highly conserved zinc finger domain within Runx1t1. Deletion of one Runx1t1 allele in an independent Runx1t1 knockout mouse model is also sufficient to prevent MYCN-driven neuroblastoma development, and reverse ganglia hyperplasia, a known pre-requisite for tumorigenesis. Silencing RUNX1T1 in human neuroblastoma cells decreases colony formation in vitro, and inhibits tumor growth in vivo. Moreover, RUNX1T1 knockdown inhibits the viability of PAX3-FOXO1 fusion-driven rhabdomyosarcoma and MYC-driven small cell lung cancer cells. Despite the role of Runx1t1 in MYCN-driven tumorigenesis neither gene directly regulates the other. We show RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex recruited by HAND2 to enhancer regions to regulate chromatin accessibility and cell-fate pathway genes.

Published
2024
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2. MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

Author

Ling Tao, Mahmoud A. Mohammad, Giorgio Milazzo, Myrthala Moreno-Smith, Tajhal D. Patel, Barry Zorman, Andrew Badachhape, Blanca E. Hernandez, Amber B. Wolf, Zihua Zeng, Jennifer H. Foster, Sara Aloisi, Pavel Sumazin, Youli Zu, John Hicks, Ketan B. Ghaghada, Nagireddy Putluri, Giovanni Perini, Cristian Coarfa, and Eveline Barbieri

Subjects
Science
Abstract

Half of high-risk neuroblastoma patients have MYCN amplification. Here, the authors show that MYCN induces fatty acid uptake and synthesis to support neuroblastoma and inhibition of a fatty acid transporter impairs tumor progression in preclinical models.

Published
2022
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3. Restoration of the molecular clock is tumor suppressive in neuroblastoma

Author

Myrthala Moreno-Smith, Giorgio Milazzo, Ling Tao, Baharan Fekry, Bokai Zhu, Mahmoud A. Mohammad, Simone Di Giacomo, Roshan Borkar, Karthik Reddy Kami Reddy, Mario Capasso, Sanjeev A. Vasudevan, Pavel Sumazin, John Hicks, Nagireddy Putluri, Giovanni Perini, Kristin Eckel-Mahan, Thomas P. Burris, and Eveline Barbieri

Subjects
Science
Abstract

MYCN is frequently amplified in neuroblastomas. Here, the authors show that MYCN disrupts the molecular clock by downregulating clock activator RORα and that the reactivation of RORα restores BMAL1 activity, and inhibits lipid metabolism and neuroblastoma growth

Published
2021
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4. PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis

Author

Slim Mzoughi, Jia Yi Fong, David Papadopoli, Cheryl M. Koh, Laura Hulea, Paolo Pigini, Federico Di Tullio, Giuseppe Andreacchio, Michal Marek Hoppe, Heike Wollmann, Diana Low, Matias J. Caldez, Yanfen Peng, Denis Torre, Julia N. Zhao, Oro Uchenunu, Gabriele Varano, Corina-Mihaela Motofeanu, Manikandan Lakshmanan, Shun Xie Teo, Cheng Mun Wun, Giovanni Perini, Soo Yong Tan, Chee Bing Ong, Muthafar Al-Haddawi, Ravisankar Rajarethinam, Susan Swee-Shan Hue, Soon Thye Lim, Choon Kiat Ong, Dachuan Huang, Siok-Bian Ng, Emily Bernstein, Dan Hasson, Keng Boon Wee, Philipp Kaldis, Anand Jeyasekharan, David Dominguez-sola, Ivan Topisirovic, and Ernesto Guccione

Subjects
Science
Abstract

The transcriptional regulator PRDM15 is expressed at low levels in normal tissues but overexpressed in B-cell lymphomas. Here, the authors show that PRDM15 depletion does not affect adult somatic cell homeostasis but leads to a metabolic crisis which impairs B-cell lymphomagenesis.

Published
2020
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5. CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming

Author

Ling Tao, Myrthala Moreno‐Smith, Rodrigo Ibarra‐García‐Padilla, Giorgio Milazzo, Nathan A. Drolet, Blanca E. Hernandez, Young S. Oh, Ivanshi Patel, Jean J. Kim, Barry Zorman, Tajhal Patel, Abu Hena Mostafa Kamal, Yanling Zhao, John Hicks, Sanjeev A. Vasudevan, Nagireddy Putluri, Cristian Coarfa, Pavel Sumazin, Giovanni Perini, Ronald J. Parchem, Rosa A. Uribe, and Eveline Barbieri

Subjects
CHAF1A, metabolism, neural crest differentiation, neuroblastoma, Science
Abstract

Abstract Neuroblastoma (NB) arises from oncogenic disruption of neural crest (NC) differentiation. Treatment with retinoic acid (RA) to induce differentiation has improved survival in some NB patients, but not all patients respond, and most NBs eventually develop resistance to RA. Loss of the chromatin modifier chromatin assembly factor 1 subunit p150 (CHAF1A) promotes NB cell differentiation; however, the mechanism by which CHAF1A drives NB oncogenesis has remained unexplored. This study shows that CHAF1A gain‐of‐function supports cell malignancy, blocks neuronal differentiation in three models (zebrafish NC, human NC, and human NB), and promotes NB oncogenesis. Mechanistically, CHAF1A upregulates polyamine metabolism, which blocks neuronal differentiation and promotes cell cycle progression. Targeting polyamine synthesis promotes NB differentiation and enhances the anti‐tumor activity of RA. The authors' results provide insight into the mechanisms that drive NB oncogenesis and suggest a rapidly translatable therapeutic approach (DFMO plus RA) to enhance the clinical efficacy of differentiation therapy in NB patients.

Published
2021
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6. The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35

Author

Pei Y. Liu, Andrew E. Tee, Giorgio Milazzo, Katherine M. Hannan, Jesper Maag, Sujanna Mondal, Bernard Atmadibrata, Nenad Bartonicek, Hui Peng, Nicholas Ho, Chelsea Mayoh, Roberto Ciaccio, Yuting Sun, Michelle J. Henderson, Jixuan Gao, Celine Everaert, Amy J. Hulme, Matthew Wong, Qing Lan, Belamy B. Cheung, Leming Shi, Jenny Y. Wang, Thorsten Simon, Matthias Fischer, Xu D. Zhang, Glenn M. Marshall, Murray D. Norris, Michelle Haber, Jo Vandesompele, Jinyan Li, Pieter Mestdagh, Ross D. Hannan, Marcel E. Dinger, Giovanni Perini, and Tao Liu

Subjects
Science
Abstract

MYCN amplification is common in neuroblastomas. Here, the authors identify a long noncoding RNA, lncNB1 in these cancers and show that it promotes tumorigenesis by binding to ribosomal protein, RPL35 to enhance E2F1 and DEPDC1B protein synthesis, which phosphorylates ERK to stabilise N-Myc.

Published
2019
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7. JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma

Author

Matthew Wong, Yuting Sun, Zhichao Xi, Giorgio Milazzo, Rebecca C. Poulos, Christoph Bartenhagen, Jessica L. Bell, Chelsea Mayoh, Nicholas Ho, Andrew E. Tee, Xiaoqiong Chen, Yang Li, Roberto Ciaccio, Pei Y. Liu, Chen C. Jiang, Qing Lan, Nisitha Jayatilleke, Belamy B. Cheung, Michelle Haber, Murray D. Norris, Xu D. Zhang, Glenn M. Marshall, Jenny Y. Wang, Stefan Hüttelmaier, Matthias Fischer, Jason W. H. Wong, Hongxi Xu, Giovanni Perini, Qihan Dong, Rani E. George, and Tao Liu

Subjects
Science
Abstract

Although the gain in chromosome 17q21-ter is commonly associated with neuroblastoma, it is not clear which gene of this region mediates tumorigenesis. Here, the authors are showing that JMJD6, which locates in that region, is a neuroblastoma tumorigenic factor.

Published
2019
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8. A new BCR-ABL1 Drosophila model as a powerful tool to elucidate the pathogenesis and progression of chronic myeloid leukemia

Author

Roberto Bernardoni, Giorgia Giordani, Elisabetta Signorino, Sara Monticelli, Francesca Messa, Monica Pradotto, Valentina Rosso, Enrico Bracco, Angela Giangrande, Giovanni Perini, Giuseppe Saglio, and Daniela Cilloni

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

The oncoprotein BCR-ABL1 triggers chronic myeloid leukemia. It is clear that the disease relies on constitutive BCR-ABL1 kinase activity, but not all the interactors and regulators of the oncoprotein are known. We describe and validate a Drosophila leukemia model based on inducible human BCR-ABL1 expression controlled by tissue-specific promoters. The model was conceived to be a versatile tool for performing genetic screens. BCR-ABL1 expression in the developing eye interferes with ommatidia differentiation and expression in the hematopoietic precursors increases the number of circulating blood cells. We show that BCR-ABL1 interferes with the pathway of endogenous dAbl with which it shares the target protein Ena. Loss of function of ena or Dab, an upstream regulator of dAbl, respectively suppresses or enhances both the BCR-ABL1-dependent phenotypes. Importantly, in patients with leukemia decreased human Dab1 and Dab2 expression correlates with more severe disease and Dab1 expression reduces the proliferation of leukemia cells. Globally, these observations validate our Drosophila model, which promises to be an excellent system for performing unbiased genetic screens aimed at identifying new BCR-ABL1 interactors and regulators in order to better elucidate the mechanism of leukemia onset and progression.

Published
2019
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9. Single-Cell Gene Network Analysis and Transcriptional Landscape of MYCN-Amplified Neuroblastoma Cell Lines

Author

Daniele Mercatelli, Nicola Balboni, Alessandro Palma, Emanuela Aleo, Pietro Paolo Sanna, Giovanni Perini, and Federico Manuel Giorgi

Subjects
neuroblastoma, gene networks, single-cell, transcriptomics, master regulator analysis, Microbiology, QR1-502
Abstract

Neuroblastoma (NBL) is a pediatric cancer responsible for more than 15% of cancer deaths in children, with 800 new cases each year in the United States alone. Genomic amplification of the MYC oncogene family member MYCN characterizes a subset of high-risk pediatric neuroblastomas. Several cellular models have been implemented to study this disease over the years. Two of these, SK-N-BE-2-C (BE2C) and Kelly, are amongst the most used worldwide as models of MYCN-Amplified human NBL. Here, we provide a transcriptome-wide quantitative measurement of gene expression and transcriptional network activity in BE2C and Kelly cell lines at an unprecedented single-cell resolution. We obtained 1105 Kelly and 962 BE2C unsynchronized cells, with an average number of mapped reads/cell of roughly 38,000. The single-cell data recapitulate gene expression signatures previously generated from bulk RNA-Seq. We highlight low variance for commonly used housekeeping genes between different cells (ACTB, B2M and GAPDH), while showing higher than expected variance for metallothionein transcripts in Kelly cells. The high number of samples, despite the relatively low read coverage of single cells, allowed for robust pathway enrichment analysis and master regulator analysis (MRA), both of which highlight the more mesenchymal nature of BE2C cells as compared to Kelly cells, and the upregulation of TWIST1 and DNAJC1 transcriptional networks. We further defined master regulators at the single cell level and showed that MYCN is not constantly active or expressed within Kelly and BE2C cells, independently of cell cycle phase. The dataset, alongside a detailed and commented programming protocol to analyze it, is fully shared and reusable.

Published
2021
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10. Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy

Author

Sabrina Angelini, Simona Soverini, Gloria Ravegnini, Matt Barnett, Eleonora Turrini, Mark Thornquist, Fabrizio Pane, Timothy P. Hughes, Deborah L. White, Jerald Radich, Dong Wook Kim, Giuseppe Saglio, Daniela Cilloni, Ilaria Iacobucci, Giovanni Perini, Richard Woodman, Giorgio Cantelli-Forti, Michele Baccarani, Patrizia Hrelia, and Giovanni Martinelli

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Imatinib has so far been the first-choice treatment in chronic myeloid leukemia with excellent results. However, only a proportion of patients achieve major molecular response – hence the need to find biological predictors of outcome to select the optimal therapeutic strategy now that more potent inhibitors are available. We investigated a panel of 20 polymorphisms in seven genes, potentially associated with the pharmacogenetics of imatinib, in a subset of 189 patients with newly diagnosed chronic myeloid leukemia enrolled in the TOPS trial. The analysis included polymorphisms in the transporters hOCT1, MDR1, ABCG2, OCTN1, and OATP1A2, and in the metabolizing genes CYP3A4 and CYP3A5. In the overall population, the OCTN1 C allele (rs1050152), a simple combination of polymorphisms in the hOCT1 gene and another combination in the genes involved in imatinib uptake were significantly associated with major molecular response. The combination of polymorphisms in imatinib uptake was also significantly associated with complete molecular response. Analyses restricted to Caucasians highlighted the significant association of MDR1 CC (rs60023214) genotype with complete molecular response. We demonstrate the usefulness of a pharmacogenetic approach for stratifying patients with chronic myeloid leukemia according to their likelihood of achieving a major or complete molecular response to imatinib. This represents an attractive opportunity for therapy optimization, worth testing in clinical trials.

Published
2013
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11. A critical appraisal of tools available for monitoring epigenetic changes in clinical samples from patients with myeloid malignancies

Author

Kirsten Grønbæk, Carsten Müller-Tidow, Giovanni Perini, Sören Lehmann, Marianne Bach Treppendahl, Ken Mills, Christoph Plass, and Brigitte Schlegelberger

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Research over the past decade has confirmed that epigenetic alterations act in concert with genetic lesions to deregulate gene expression in acute myeloid leukemia and myelodysplastic syndromes. Epigenetic alterations may serve as markers of disease, and may potentially be used for classification, prognostication and to monitor minimal residual disease. In addition, we now have the capability to pharmaceutically target epigenetic modifications, and there is an urgent need for early validation of the efficacy of the drugs. Also, an improved understanding of the functionality of epigenetic modifications may further pave the road towards individualized therapy. The recent advances in biotechnology and bioinformatics provide a plethora of novel tools for characterizing the epigenome in clinical samples, but at this point the practical, clinical utility of these methodologies needs further exploration. Here, we provide the pros and cons of the currently most feasible methods used for characterizing the methylome in clinical samples, and give a brief introduction to novel approaches to sequencing that may revolutionize our abilities to characterize the genomes and epigenomes in acute myeloid leukemia and myelodysplastic syndrome patients.

Published
2012
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12. IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia.

Author

Ilaria Iacobucci, Nunzio Iraci, Monica Messina, Annalisa Lonetti, Sabina Chiaretti, Emanuele Valli, Anna Ferrari, Cristina Papayannidis, Francesca Paoloni, Antonella Vitale, Clelia Tiziana Storlazzi, Emanuela Ottaviani, Viviana Guadagnuolo, Sandra Durante, Marco Vignetti, Simona Soverini, Fabrizio Pane, Robin Foà, Michele Baccarani, Markus Müschen, Giovanni Perini, and Giovanni Martinelli

Subjects
Medicine, Science
Abstract

Deletions of IKAROS (IKZF1) frequently occur in B-cell precursor acute lymphoblastic leukemia (B-ALL) but the mechanisms by which they influence pathogenesis are unclear. To address this issue, a cohort of 144 adult B-ALL patients (106 BCR-ABL1-positive and 38 B-ALL negative for known molecular rearrangements) was screened for IKZF1 deletions by single nucleotide polymorphism (SNP) arrays; a sub-cohort of these patients (44%) was then analyzed for gene expression profiling.Total or partial deletions of IKZF1 were more frequent in BCR-ABL1-positive than in BCR-ABL1-negative B-ALL cases (75% vs 58%, respectively, p = 0.04). Comparison of the gene expression signatures of patients carrying IKZF1 deletion vs those without showed a unique signature featured by down-regulation of B-cell lineage and DNA repair genes and up-regulation of genes involved in cell cycle, JAK-STAT signalling and stem cell self-renewal. Through chromatin immunoprecipitation and luciferase reporter assays we corroborated these findings both in vivo and in vitro, showing that Ikaros deleted isoforms lacked the ability to directly regulate a large group of the genes in the signature, such as IGLL1, BLK, EBF1, MSH2, BUB3, ETV6, YES1, CDKN1A (p21), CDKN2C (p18) and MCL1.Here we identified and validated for the first time molecular pathways specifically controlled by IKZF1, shedding light into IKZF1 role in B-ALL pathogenesis.

Published
2012
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13. The DMD locus harbours multiple long non-coding RNAs which orchestrate and control transcription of muscle dystrophin mRNA isoforms.

Author

Matteo Bovolenta, Daniela Erriquez, Emanuele Valli, Simona Brioschi, Chiara Scotton, Marcella Neri, Maria Sofia Falzarano, Samuele Gherardi, Marina Fabris, Paola Rimessi, Francesca Gualandi, Giovanni Perini, and Alessandra Ferlini

Subjects
Medicine, Science
Abstract

The 2.2 Mb long dystrophin (DMD) gene, the largest gene in the human genome, corresponds to roughly 0.1% of the entire human DNA sequence. Mutations in this gene cause Duchenne muscular dystrophy and other milder X-linked, recessive dystrophinopathies. Using a custom-made tiling array, specifically designed for the DMD locus, we identified a variety of novel long non-coding RNAs (lncRNAs), both sense and antisense oriented, whose expression profiles mirror that of DMD gene. Importantly, these transcripts are intronic in origin and specifically localized to the nucleus and are transcribed contextually with dystrophin isoforms or primed by MyoD-induced myogenic differentiation. Furthermore, their forced ectopic expression in both human muscle and neuronal cells causes a specific and negative regulation of endogenous dystrophin full length isoforms and significantly down-regulate the activity of a luciferase reporter construct carrying the minimal promoter regions of the muscle dystrophin isoform. Consistent with this apparently repressive role, we found that, in muscle samples of dystrophinopathic female carriers, lncRNAs expression levels inversely correlate with those of muscle full length DMD isoforms. Overall these findings unveil an unprecedented complexity of the transcriptional pattern of the DMD locus and reveal that DMD lncRNAs may contribute to the orchestration and homeostasis of the muscle dystrophin expression pattern by either selective targeting and down-modulating the dystrophin promoter transcriptional activity.

Published
2012
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14. SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability.

Author

Glenn M Marshall, Pei Y Liu, Samuele Gherardi, Christopher J Scarlett, Antonio Bedalov, Ning Xu, Nuncio Iraci, Emanuele Valli, Dora Ling, Wayne Thomas, Margo van Bekkum, Eric Sekyere, Kacper Jankowski, Toby Trahair, Karen L Mackenzie, Michelle Haber, Murray D Norris, Andrew V Biankin, Giovanni Perini, and Tao Liu

Subjects
Genetics, QH426-470
Abstract

The N-Myc oncoprotein is a critical factor in neuroblastoma tumorigenesis which requires additional mechanisms converting a low-level to a high-level N-Myc expression. N-Myc protein is stabilized when phosphorylated at Serine 62 by phosphorylated ERK protein. Here we describe a novel positive feedback loop whereby N-Myc directly induced the transcription of the class III histone deacetylase SIRT1, which in turn increased N-Myc protein stability. SIRT1 binds to Myc Box I domain of N-Myc protein to form a novel transcriptional repressor complex at gene promoter of mitogen-activated protein kinase phosphatase 3 (MKP3), leading to transcriptional repression of MKP3, ERK protein phosphorylation, N-Myc protein phosphorylation at Serine 62, and N-Myc protein stabilization. Importantly, SIRT1 was up-regulated, MKP3 down-regulated, in pre-cancerous cells, and preventative treatment with the SIRT1 inhibitor Cambinol reduced tumorigenesis in TH-MYCN transgenic mice. Our data demonstrate the important roles of SIRT1 in N-Myc oncogenesis and SIRT1 inhibitors in the prevention and therapy of N-Myc-induced neuroblastoma.

Published
2011
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15. The C-terminal domain of CENP-C displays multiple and critical functions for mammalian centromere formation.

Author

Stefania Trazzi, Giovanni Perini, Roberto Bernardoni, Monica Zoli, Joseph C Reese, Andrea Musacchio, and Giuliano Della Valle

Subjects
Medicine, Science
Abstract

CENP-C is a fundamental component of functional centromeres. The elucidation of its structure-function relationship with centromeric DNA and other kinetochore proteins is critical to the understanding of centromere assembly. CENP-C carries two regions, the central and the C-terminal domains, both of which are important for the ability of CENP-C to associate with the centromeric DNA. However, while the central region is largely divergent in CENP-C homologues, the C-terminal moiety contains two regions that are highly conserved from yeast to humans, named Mif2p homology domains (blocks II and III). The activity of these two domains in human CENP-C is not well defined. In this study we performed a functional dissection of C-terminal CENP-C region analyzing the role of single Mif2p homology domains through in vivo and in vitro assays. By immunofluorescence and Chromatin immunoprecipitation assay (ChIP) we were able to elucidate the ability of the Mif2p homology domain II to target centromere and contact alpha satellite DNA. We also investigate the interactions with other conserved inner kinetochore proteins by means of coimmunoprecipitation and bimolecular fluorescence complementation on cell nuclei. We found that the C-terminal region of CENP-C (Mif2p homology domain III) displays multiple activities ranging from the ability to form higher order structures like homo-dimers and homo-oligomers, to mediate interaction with CENP-A and histone H3. Overall, our findings support a model in which the Mif2p homology domains of CENP-C, by virtue of their ability to establish multiple contacts with DNA and centromere proteins, play a critical role in the structuring of kinethocore chromatin.

Published
2009
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16. Supplementary Figures 1-4, Tables 1-2 from c-MYC Oncoprotein Dictates Transcriptional Profiles of ATP-Binding Cassette Transporter Genes in Chronic Myelogenous Leukemia CD34+ Hematopoietic Progenitor Cells

Author

Giovanni Perini, Giovanni Martinelli, Michele Baccarani, Murray D. Norris, Michelle Haber, Chiara Perrod, Roberto Bernardoni, Thea Kalebic, Emanuele Valli, Sandra Durante, Carolina Terragna, Samuele Gherardi, Daniel Diolaiti, Simona Soverini, Nunzio Iraci, and Antonio Porro

Abstract

PDF file - 2651K

Published
2023
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17. Data from The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription

Author

Tao Liu, Christopher J. Scarlett, Giovanni Perini, Patsie Polly, Jenny Wang, Jason W.H. Wong, Stefan Hüttelmaier, Xu Dong Zhang, Pei Yan Liu, Dora Ling, Nicholas Ho, Duohui Jing, Yuting Sun, Bernard Atmadibrata, Rebecca C. Poulos, Jessica L. Bell, Giorgio Milazzo, Andrew E.L. Tee, and Matthew Wong

Abstract

Myc oncoproteins exert tumorigenic effects by regulating expression of target oncogenes. Histone H3 lysine 79 (H3K79) methylation at Myc-responsive elements of target gene promoters is a strict prerequisite for Myc-induced transcriptional activation, and DOT1L is the only known histone methyltransferase that catalyzes H3K79 methylation. Here, we show that N-Myc upregulates DOT1L mRNA and protein expression by binding to the DOT1L gene promoter. shRNA-mediated depletion of DOT1L reduced mRNA and protein expression of N-Myc target genes ODC1 and E2F2. DOT1L bound to the Myc Box II domain of N-Myc protein, and knockdown of DOT1L reduced histone H3K79 methylation and N-Myc protein binding at the ODC1 and E2F2 gene promoters and reduced neuroblastoma cell proliferation. Treatment with the small-molecule DOT1L inhibitor SGC0946 reduced H3K79 methylation and proliferation of MYCN gene–amplified neuroblastoma cells. In mice xenografts of neuroblastoma cells stably expressing doxycycline-inducible DOT1L shRNA, ablating DOT1L expression with doxycycline significantly reduced ODC1 and E2F2 expression, reduced tumor progression, and improved overall survival. In addition, high levels of DOT1L gene expression in human neuroblastoma tissues correlated with high levels of MYCN, ODC1, and E2F2 gene expression and independently correlated with poor patient survival. Taken together, our results identify DOT1L as a novel cofactor in N-Myc–mediated transcriptional activation of target genes and neuroblastoma oncogenesis. Furthermore, they characterize DOT1L inhibitors as novel anticancer agents against MYCN-amplified neuroblastoma. Cancer Res; 77(9); 2522–33. ©2017 AACR.

Published
2023
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18. Supplementary Figure S1 A-E from Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Author

Glenn M. Marshall, Belamy B. Cheung, Michael W. Parker, Giovanni Perini, Jamie I. Fletcher, Murray D. Norris, Michelle Haber, W. Clay Gustafson, Shizhen Zhu, Xiaoling Zhang, Tao Liu, Andrew J. Gifford, Matthias Fischer, Andre Oberthuer, Stefan Hüttelmaier, Larissa Doughty, Jessica L. Bell, Michael A. Gorman, Brendan W. Stevenson, Bryce Keenan, Chelsea Mayoh, Bing Liu, Joshua A. McCarroll, Jayne E. Murray, Giorgio Milazzo, Janith A. Seneviratne, Taylor Lim, Mika Herath, Olivia C. Ciampa, Daniel R. Carter, Hassina Massudi, Jessica K. Holien, and Jessica Koach

Abstract

Supplementary Figure S1. PA2G4 is a MYCN transactivation target gene. A, Quantification of protein expression using anti-PA2G4 and anti-MYCN antibodies against whole cell protein lysates from BE(2)-C and Kelly cells, following MYCN siRNA knockdown for 48 hours. B, mRNA expression of PA2G4 and MYCN in SH-EP MYCN3 overexpression cells treated with 1µg/ml doxycycline for 24-96 hr. C, The effect of doxycycline-induced MYCN overexpression in SHEP-TRE-MYCN cells on c-MYC and PA2G4 protein expression. D, Chromatin immunoprecipitation (ChIP) assay in Kelly cells using an anti-MYCN antibody, and real-time PCR analysis with primers identifying the MYCN DNA binding sites in the PA2G4 gene promoter (500bP upstream of transcription start site [TSS]) or Intron 1a & 1b regions of the PA2G4 gene, with and without MYCN siRNA knockdown. ChIP and real-time PCR analysis using primers against a region 1200bp upstream of TSS was used as a negative control for MYCN chromatin binding. ChIP and real-time PCR analysis using primers against the ornithine decarboxylase (ODC1) gene promoter region was used as a positive control for MYCN chromatin binding. E, Immunoblot analysis of PA2G4, MYCN and MYC protein levels in a panel of human MYCN amplified and non-amplified neuroblastoma, and normal fibroblast, cell lines using antibodies recognising PA2G4, MYCN and MYC.

Published
2023
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19. Supplementary Figure S1 F-I from Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Author

Glenn M. Marshall, Belamy B. Cheung, Michael W. Parker, Giovanni Perini, Jamie I. Fletcher, Murray D. Norris, Michelle Haber, W. Clay Gustafson, Shizhen Zhu, Xiaoling Zhang, Tao Liu, Andrew J. Gifford, Matthias Fischer, Andre Oberthuer, Stefan Hüttelmaier, Larissa Doughty, Jessica L. Bell, Michael A. Gorman, Brendan W. Stevenson, Bryce Keenan, Chelsea Mayoh, Bing Liu, Joshua A. McCarroll, Jayne E. Murray, Giorgio Milazzo, Janith A. Seneviratne, Taylor Lim, Mika Herath, Olivia C. Ciampa, Daniel R. Carter, Hassina Massudi, Jessica K. Holien, and Jessica Koach

Abstract

Supplementary Figure S1. F, Confocal microscopy of SHEP Tet21N cells using anti-PA2G4 (red) and anti-MYCN (green) antibodies. G, Immunoblot analysis of cytoplasmic and nuclear fractions from BE(2)-C and Kelly human neuroblastoma cell lines with antibodies recognizing PA2G4 and MYCN, or GAPDH and topoisomerase as loading controls. H, Confocal microscopy of neuroblastoma (BE(2)-C and Kelly) cells using anti-PA2G4 (red) and anti-MYCN (green) antibodies. Alexafluor 555 anti-rabbit (to detect PA2G4) and Alexafluor 488 anti-mouse (to detect MYCN) were used as the secondary antibodies. I, Real-time PCR mRNA expression of MYCN and PA2G4 in ganglia from homozygote TH-MYCN+/+ mice, compared to wild type littermate control mice, obtained at different postnatal age (weeks).

Published
2023
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20. Data from Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Author

Glenn M. Marshall, Belamy B. Cheung, Michael W. Parker, Giovanni Perini, Jamie I. Fletcher, Murray D. Norris, Michelle Haber, W. Clay Gustafson, Shizhen Zhu, Xiaoling Zhang, Tao Liu, Andrew J. Gifford, Matthias Fischer, Andre Oberthuer, Stefan Hüttelmaier, Larissa Doughty, Jessica L. Bell, Michael A. Gorman, Brendan W. Stevenson, Bryce Keenan, Chelsea Mayoh, Bing Liu, Joshua A. McCarroll, Jayne E. Murray, Giorgio Milazzo, Janith A. Seneviratne, Taylor Lim, Mika Herath, Olivia C. Ciampa, Daniel R. Carter, Hassina Massudi, Jessica K. Holien, and Jessica Koach

Abstract

MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN–PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN–PA2G4 protein–protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease.Significance:Competitive chemical inhibition of the PA2G4–MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

Published
2023
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21. Supplementary Figure S2A-C from Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Author

Glenn M. Marshall, Belamy B. Cheung, Michael W. Parker, Giovanni Perini, Jamie I. Fletcher, Murray D. Norris, Michelle Haber, W. Clay Gustafson, Shizhen Zhu, Xiaoling Zhang, Tao Liu, Andrew J. Gifford, Matthias Fischer, Andre Oberthuer, Stefan Hüttelmaier, Larissa Doughty, Jessica L. Bell, Michael A. Gorman, Brendan W. Stevenson, Bryce Keenan, Chelsea Mayoh, Bing Liu, Joshua A. McCarroll, Jayne E. Murray, Giorgio Milazzo, Janith A. Seneviratne, Taylor Lim, Mika Herath, Olivia C. Ciampa, Daniel R. Carter, Hassina Massudi, Jessica K. Holien, and Jessica Koach

Abstract

Supplementary Figure S2. PA2G4 increases MYCN protein stability. A and B, Representative immunoblots from cycloheximide (CHX) chase assays measuring the half-life of MYCN protein after PA2G4 knockdown (A) or overexpression (B) in BE(2)-C and Kelly cells for 48 hours. Cells were then treated with 100 µg/µl CHX for up to 60 minutes followed by immunoblotting. C, Co-IP of total protein from BE(2)-C cells using IgG, anti-MYCN, anti-PA2G4 antibodies, followed by immunoblotting with anti-MYCN, anti-PA2G4, anti-AURKA, anti-Fbxw7 or anti-vinculin antibodies.

Published
2023
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22. Supplementary Information from Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Author

Glenn M. Marshall, Belamy B. Cheung, Michael W. Parker, Giovanni Perini, Jamie I. Fletcher, Murray D. Norris, Michelle Haber, W. Clay Gustafson, Shizhen Zhu, Xiaoling Zhang, Tao Liu, Andrew J. Gifford, Matthias Fischer, Andre Oberthuer, Stefan Hüttelmaier, Larissa Doughty, Jessica L. Bell, Michael A. Gorman, Brendan W. Stevenson, Bryce Keenan, Chelsea Mayoh, Bing Liu, Joshua A. McCarroll, Jayne E. Murray, Giorgio Milazzo, Janith A. Seneviratne, Taylor Lim, Mika Herath, Olivia C. Ciampa, Daniel R. Carter, Hassina Massudi, Jessica K. Holien, and Jessica Koach

Abstract

Supplementary Information

Published
2023
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23. Supplementary Figure S6 A-F from Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Author

Glenn M. Marshall, Belamy B. Cheung, Michael W. Parker, Giovanni Perini, Jamie I. Fletcher, Murray D. Norris, Michelle Haber, W. Clay Gustafson, Shizhen Zhu, Xiaoling Zhang, Tao Liu, Andrew J. Gifford, Matthias Fischer, Andre Oberthuer, Stefan Hüttelmaier, Larissa Doughty, Jessica L. Bell, Michael A. Gorman, Brendan W. Stevenson, Bryce Keenan, Chelsea Mayoh, Bing Liu, Joshua A. McCarroll, Jayne E. Murray, Giorgio Milazzo, Janith A. Seneviratne, Taylor Lim, Mika Herath, Olivia C. Ciampa, Daniel R. Carter, Hassina Massudi, Jessica K. Holien, and Jessica Koach

Abstract

Supplementary Figure S6. PA2G4 increases neuroblastoma tumorigenicity. A, Representative images of athymic nude mice inoculated with neuroblastoma (SH-EP) cells stably transfected with either EV control or a PA2G4 expression vector at 10 weeks post-injection. B, Images of tumor formation after mice were culled 12 weeks post-injection. C, Real-time PCR analysis of PA2G4 mRNA expression level in tumors from mice injected with either SH-EP cells overexpressing PA2G4, or SH-EP EV control cells. β2-microglobulin was used as a reference gene for total RNA loading. D, Protein was extracted from SH-EP tumor xenografts overexpressing PA2G4 and control vectors, then analysed for PA2G4-Flag and MYCN expression by immunoblotting using anti-MYCN and anti-PA2G4 antibodies, using a Vinculin loading control. E, Immunoblots of three tumor samples from each siRNA-treated cohort showing the levels of PA2G4 and MYCN protein expression, using a Vinculin loading control. F, Real-time PCR analysis of PA2G4 and MYCN mRNA expression in tumor samples taken from tumour-bearing mice xenografted with BE(2)-C neuroblastoma cells, which had been treated with either nano-particle encapsulated siRNA control, PA2G4 siRNA or PA2G4-p48 siRNA. Data are shown as means and SD derived from 6 mice per group, P-values were calculated by t-test.

Published
2023
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24. Supplementary Figure S5 F-H from Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Author

Glenn M. Marshall, Belamy B. Cheung, Michael W. Parker, Giovanni Perini, Jamie I. Fletcher, Murray D. Norris, Michelle Haber, W. Clay Gustafson, Shizhen Zhu, Xiaoling Zhang, Tao Liu, Andrew J. Gifford, Matthias Fischer, Andre Oberthuer, Stefan Hüttelmaier, Larissa Doughty, Jessica L. Bell, Michael A. Gorman, Brendan W. Stevenson, Bryce Keenan, Chelsea Mayoh, Bing Liu, Joshua A. McCarroll, Jayne E. Murray, Giorgio Milazzo, Janith A. Seneviratne, Taylor Lim, Mika Herath, Olivia C. Ciampa, Daniel R. Carter, Hassina Massudi, Jessica K. Holien, and Jessica Koach

Abstract

Supplementary Figure S5 F-H F), at 72 hours post-transfection of EV or a PA2G4 expression vector. G, Cell viability measured by the Alamar Blue assay and immunoblot analyses using an antibody identifying MYC-tagged PA2G4-p42 protein expression in Kelly and SH-SY5Y cells transfected with EV or the MYC-tagged PA2G4-p42 expression vector at 48 and 72 hours post-transfection. Vinculin was used as loading control. H, Colony formation in vitro by Kelly and SH-SY5Y cells following transfection with either EV or MYC-tagged PA2G4-p42.

Published
2023
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25. Supplementary Figure S3 F-G from Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Author

Glenn M. Marshall, Belamy B. Cheung, Michael W. Parker, Giovanni Perini, Jamie I. Fletcher, Murray D. Norris, Michelle Haber, W. Clay Gustafson, Shizhen Zhu, Xiaoling Zhang, Tao Liu, Andrew J. Gifford, Matthias Fischer, Andre Oberthuer, Stefan Hüttelmaier, Larissa Doughty, Jessica L. Bell, Michael A. Gorman, Brendan W. Stevenson, Bryce Keenan, Chelsea Mayoh, Bing Liu, Joshua A. McCarroll, Jayne E. Murray, Giorgio Milazzo, Janith A. Seneviratne, Taylor Lim, Mika Herath, Olivia C. Ciampa, Daniel R. Carter, Hassina Massudi, Jessica K. Holien, and Jessica Koach

Abstract

Supplementary Figure S3 F-G F, Left panel: Histopathologic and immunohistochemical analyses of MYCN;GFP tumors treated with vehicle (left) or WS6 (right). Left Panel, Top to Bottom: Neuroblastoma tumour sections immunohistochemically stained for Haematoxylin & Eosin (H&E), Proliferating Cell Nuclear Antigen (pCNA), Neural Hu protein C (Hu-C), MYCN, PA2G4 and Tyrosine Hydroxylase. Scale bar, 50 μm. Right Panel: Histograms illustrating the staining intensity of cells of vehicle (left) or WS6 treated neuroblastoma tumours expressing either MYCN, PA2G4 or Tyrosine Hydroxylase as measured by Image J software. Sample means (horizontal bars) were compared by students t-test (two-tailed). *** represents p-value

Published
2023
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26. Supplementary Table S2 from The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription

Author

Tao Liu, Christopher J. Scarlett, Giovanni Perini, Patsie Polly, Jenny Wang, Jason W.H. Wong, Stefan Hüttelmaier, Xu Dong Zhang, Pei Yan Liu, Dora Ling, Nicholas Ho, Duohui Jing, Yuting Sun, Bernard Atmadibrata, Rebecca C. Poulos, Jessica L. Bell, Giorgio Milazzo, Andrew E.L. Tee, and Matthew Wong

Abstract

Supplementary Table S2. Multivariable Cox regression analysis of DOT1L expression in tumor tissues as a factor prognostic for outcome in 476 neuroblastoma patients

Published
2023
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27. Supplementary Table S1 (Excel file) from The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription

Author

Tao Liu, Christopher J. Scarlett, Giovanni Perini, Patsie Polly, Jenny Wang, Jason W.H. Wong, Stefan Hüttelmaier, Xu Dong Zhang, Pei Yan Liu, Dora Ling, Nicholas Ho, Duohui Jing, Yuting Sun, Bernard Atmadibrata, Rebecca C. Poulos, Jessica L. Bell, Giorgio Milazzo, Andrew E.L. Tee, and Matthew Wong

Abstract

Supplementary Table S1 (Excel file). List of transcription factor target motifs around transcription start sites of genes down-regulated by DOT1L shRNA, as identified by gene set enrichment analysis.

Published
2023
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28. Supplementary Figure S6 G-K from Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Author

Glenn M. Marshall, Belamy B. Cheung, Michael W. Parker, Giovanni Perini, Jamie I. Fletcher, Murray D. Norris, Michelle Haber, W. Clay Gustafson, Shizhen Zhu, Xiaoling Zhang, Tao Liu, Andrew J. Gifford, Matthias Fischer, Andre Oberthuer, Stefan Hüttelmaier, Larissa Doughty, Jessica L. Bell, Michael A. Gorman, Brendan W. Stevenson, Bryce Keenan, Chelsea Mayoh, Bing Liu, Joshua A. McCarroll, Jayne E. Murray, Giorgio Milazzo, Janith A. Seneviratne, Taylor Lim, Mika Herath, Olivia C. Ciampa, Daniel R. Carter, Hassina Massudi, Jessica K. Holien, and Jessica Koach

Abstract

Supplementary Figure S6 G-K G, Overall patient survival using Kaplan-Meier survival probability plots from the Cologne data set (http://r2.amc.nl) for PA2G4 mRNA expression subdivided around the median PA2G4 expression level among 477 neuroblastoma patients. H, Kaplan-Meier plot for event-free survival of 649 neuroblastoma patients from the kocak dataset (R2 microarray analysis and visualization platform, http://r2.amc.nl) I, Real-time PCR mRNA expression of PA2G4 among 40 neuroblastoma patient tumors treated at Sydney Children's Hospital, subdivided by MYCN amplification status. J, Multivariate event-free survival analysis using cox regression modelling. The p-values were obtained from the cox-regression analysis. K, Incidence of PA2G4 amplification among a range of different human cancer types within The Cancer Genome Atlas (TCGA). Results were generated using cBioportal for Cancer Genomics (https://cancergenome.nih.gov/). NEPC, neuroendocrine prostate cancer; CS, carcinosarcoma.

Published
2023
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29. Supplementary Materials and Methods, Figures, Figure Legends - Revised from The Histone Methyltransferase DOT1L Promotes Neuroblastoma by Regulating Gene Transcription

Author

Tao Liu, Christopher J. Scarlett, Giovanni Perini, Patsie Polly, Jenny Wang, Jason W.H. Wong, Stefan Hüttelmaier, Xu Dong Zhang, Pei Yan Liu, Dora Ling, Nicholas Ho, Duohui Jing, Yuting Sun, Bernard Atmadibrata, Rebecca C. Poulos, Jessica L. Bell, Giorgio Milazzo, Andrew E.L. Tee, and Matthew Wong

Abstract

Supplementary Materials and Methods, Figures, Figure Legends. Fig. S1, N-Myc up-regulates ODC1 and E2F2. Fig. S2, DOT1L and N-Myc do not regulate HIF1α and VEGF. Fig. S3, knocking down DOT1L gene expression does not induce neuroblastoma cell death. Fig. S4, knocking down DOT1L reduces ODC1 and E2F2 expression in neuroblastoma tissues in mice. Fig. S5, DOT1L expression correlates with ODC1 and E2F2 expression in human neuroblastoma tissues.

Published
2023
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30. Supplementary Tables from MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

Author

Karen L. MacKenzie, Jamie I. Fletcher, Giovanni Perini, Murray D. Norris, Preethi H. Gunaratne, Michelle Haber, Wendy B. London, Hilda A. Pickett, Georg von Jonquieres, Claudia L. Flemming, Amanda J. Russell, Jayne Murray, Chen Yang, Stefania Purgato, Cheng Fei Kong, Bing Liu, Michelle F. Maritz, Sieu L. Tran, and Rosemary O'Brien

Abstract

Supplementary Table 1: siRNA sequences Supplementary Table 2: qRT-PCR primers Supplementary Table 3: Primers for chromatin immunoprecipitation Supplementary Table 4: Multivariate analysis of event free survival and overall survival of neuroblastoma patients

Published
2023
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31. Supplementary Dataset 2 from WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

Author

Tao Liu, Antony Braithwaite, Glenn M. Marshall, Giovanni Perini, Stefan Hüttelmaier, Karen L. MacKenzie, Masoud Vedadi, Cheryl H. Arrowsmith, Peter J. Brown, Johannes H. Schulte, Ygal Haupt, Jason M. Shohet, Quan Zhao, Toby Trahair, Matthew Wong, Bernard Atmadibrata, Bing Liu, Pei Y. Liu, Andrew E. Tee, Rima Al-Awar, Jason W.H. Wong, Giorgio Milazzo, Rebecca C. Poulos, Samuele Gherardi, Daniel Carter, Jessica L. Bell, and Yuting Sun

Abstract

List of N-Myc-binding gene promoters at which H3K4me3 was reduced by WDR5 siRNA.

Published
2023
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32. Supplementary Dataset 3 from WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

Author

Tao Liu, Antony Braithwaite, Glenn M. Marshall, Giovanni Perini, Stefan Hüttelmaier, Karen L. MacKenzie, Masoud Vedadi, Cheryl H. Arrowsmith, Peter J. Brown, Johannes H. Schulte, Ygal Haupt, Jason M. Shohet, Quan Zhao, Toby Trahair, Matthew Wong, Bernard Atmadibrata, Bing Liu, Pei Y. Liu, Andrew E. Tee, Rima Al-Awar, Jason W.H. Wong, Giorgio Milazzo, Rebecca C. Poulos, Samuele Gherardi, Daniel Carter, Jessica L. Bell, and Yuting Sun

Abstract

List of N-Myc non-binding gene promoters at which H3K4me3 was reduced by WDR5 siRNA.

Published
2023
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33. Supplementary Figures from MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

Author

Karen L. MacKenzie, Jamie I. Fletcher, Giovanni Perini, Murray D. Norris, Preethi H. Gunaratne, Michelle Haber, Wendy B. London, Hilda A. Pickett, Georg von Jonquieres, Claudia L. Flemming, Amanda J. Russell, Jayne Murray, Chen Yang, Stefania Purgato, Cheng Fei Kong, Bing Liu, Michelle F. Maritz, Sieu L. Tran, and Rosemary O'Brien

Abstract

Supporting data; Supplementary Figure 1:Correlation analysis of DKC1 mRNA and dyskerin protein quantity in neuroblastoma cell lines Supplementary Figure 2:Correlation analysis of telomerase activity gene expression in neuroblastoma cells Supplementary Figure 3:Correlation analysis of TERT and MYC gene expression in neuroblastoma tumor samples Supplementary Figure 4:High DKC1 expression is a marker of poor prognosis in neuroblastoma Supplementary Figure 5:Analysis of TERT expression in neuroblastoma tumor samples Supplementary Figure 7: Upregulation of p21cip1 in NB69, but not SK-N-BE(2) cells following down regulation of dyskerin Supplementary Figure 8: Cell cycle and viability following downregulation of dyskerin

Published
2023
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35. Supplementary Dataset 4 from WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

Author

Tao Liu, Antony Braithwaite, Glenn M. Marshall, Giovanni Perini, Stefan Hüttelmaier, Karen L. MacKenzie, Masoud Vedadi, Cheryl H. Arrowsmith, Peter J. Brown, Johannes H. Schulte, Ygal Haupt, Jason M. Shohet, Quan Zhao, Toby Trahair, Matthew Wong, Bernard Atmadibrata, Bing Liu, Pei Y. Liu, Andrew E. Tee, Rima Al-Awar, Jason W.H. Wong, Giorgio Milazzo, Rebecca C. Poulos, Samuele Gherardi, Daniel Carter, Jessica L. Bell, and Yuting Sun

Abstract

List of N-Myc-binding gene promoters at which H3K4me3 was not reduced by WDR5 siRNA.

Published
2023
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36. Supplementary Methods-Figures-Tables from WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

Author

Tao Liu, Antony Braithwaite, Glenn M. Marshall, Giovanni Perini, Stefan Hüttelmaier, Karen L. MacKenzie, Masoud Vedadi, Cheryl H. Arrowsmith, Peter J. Brown, Johannes H. Schulte, Ygal Haupt, Jason M. Shohet, Quan Zhao, Toby Trahair, Matthew Wong, Bernard Atmadibrata, Bing Liu, Pei Y. Liu, Andrew E. Tee, Rima Al-Awar, Jason W.H. Wong, Giorgio Milazzo, Rebecca C. Poulos, Samuele Gherardi, Daniel Carter, Jessica L. Bell, and Yuting Sun

Abstract

Supplementary Methods-Figures-Tables

Published
2023
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38. Supplementary Dataset 1 from WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

Author

Tao Liu, Antony Braithwaite, Glenn M. Marshall, Giovanni Perini, Stefan Hüttelmaier, Karen L. MacKenzie, Masoud Vedadi, Cheryl H. Arrowsmith, Peter J. Brown, Johannes H. Schulte, Ygal Haupt, Jason M. Shohet, Quan Zhao, Toby Trahair, Matthew Wong, Bernard Atmadibrata, Bing Liu, Pei Y. Liu, Andrew E. Tee, Rima Al-Awar, Jason W.H. Wong, Giorgio Milazzo, Rebecca C. Poulos, Samuele Gherardi, Daniel Carter, Jessica L. Bell, and Yuting Sun

Abstract

Genes differentially down- or up-regulated by WDR5 siRNAs by more than 1.5 fold, as shown by Affymetrix microarray, in BE(2)-C neuroblastoma cells 40 hours after siRNA transfection.

Published
2023
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39. Supplementary Methods from MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

Author

Karen L. MacKenzie, Jamie I. Fletcher, Giovanni Perini, Murray D. Norris, Preethi H. Gunaratne, Michelle Haber, Wendy B. London, Hilda A. Pickett, Georg von Jonquieres, Claudia L. Flemming, Amanda J. Russell, Jayne Murray, Chen Yang, Stefania Purgato, Cheng Fei Kong, Bing Liu, Michelle F. Maritz, Sieu L. Tran, and Rosemary O'Brien

Abstract

Text file containing detailed methods.

Published
2023
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40. Supplementary Dataset 5 from WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

Author

Tao Liu, Antony Braithwaite, Glenn M. Marshall, Giovanni Perini, Stefan Hüttelmaier, Karen L. MacKenzie, Masoud Vedadi, Cheryl H. Arrowsmith, Peter J. Brown, Johannes H. Schulte, Ygal Haupt, Jason M. Shohet, Quan Zhao, Toby Trahair, Matthew Wong, Bernard Atmadibrata, Bing Liu, Pei Y. Liu, Andrew E. Tee, Rima Al-Awar, Jason W.H. Wong, Giorgio Milazzo, Rebecca C. Poulos, Samuele Gherardi, Daniel Carter, Jessica L. Bell, and Yuting Sun

Abstract

List of N-Myc non-binding gene promoters at which H3K4me3 was not reduced by WDR5 siRNA.

Published
2023
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41. Data from MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

Author

Karen L. MacKenzie, Jamie I. Fletcher, Giovanni Perini, Murray D. Norris, Preethi H. Gunaratne, Michelle Haber, Wendy B. London, Hilda A. Pickett, Georg von Jonquieres, Claudia L. Flemming, Amanda J. Russell, Jayne Murray, Chen Yang, Stefania Purgato, Cheng Fei Kong, Bing Liu, Michelle F. Maritz, Sieu L. Tran, and Rosemary O'Brien

Abstract

The RNA-binding protein dyskerin, encoded by the DKC1 gene, functions as a core component of the telomerase holoenzyme as well as ribonuclear protein complexes involved in RNA processing and ribosome biogenesis. The diverse roles of dyskerin across many facets of RNA biology implicate its potential contribution to malignancy. In this study, we examined the expression and function of dyskerin in neuroblastoma. We show that DKC1 mRNA levels were elevated relative to normal cells across a panel of 15 neuroblastoma cell lines, where both N-Myc and c-Myc directly targeted the DKC1 promoter. Upregulation of MYCN was shown to dramatically increase DKC1 expression. In two independent neuroblastoma patient cohorts, high DKC1 expression correlated strongly with poor event-free and overall survival (P < 0.0001), independently of established prognostic factors. RNAi-mediated depletion of dyskerin inhibited neuroblastoma cell proliferation, including cells immortalized via the telomerase-independent ALT mechanism. Furthermore, dyskerin attenuation impaired anchorage-independent proliferation and tumor growth. Overexpression of the telomerase RNA component, hTR, demonstrated that this proliferative impairment was not a consequence of telomerase suppression. Instead, ribosomal stress, evidenced by depletion of small nucleolar RNAs and nuclear dispersal of ribosomal proteins, was the likely cause of the proliferative impairment in dyskerin-depleted cells. Accordingly, dyskerin suppression caused p53-dependent G1 cell-cycle arrest in p53 wild-type cells, and a p53-independent pathway impaired proliferation in cells with p53 dysfunction. Together, our findings highlight dyskerin as a new therapeutic target in neuroblastoma with crucial telomerase-independent functions and broader implications for the spectrum of malignancies driven by MYC family oncogenes. Cancer Res; 76(12); 3604–17. ©2016 AACR.

Published
2023
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43. Supplementary Figure Legends from MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

Author

Karen L. MacKenzie, Jamie I. Fletcher, Giovanni Perini, Murray D. Norris, Preethi H. Gunaratne, Michelle Haber, Wendy B. London, Hilda A. Pickett, Georg von Jonquieres, Claudia L. Flemming, Amanda J. Russell, Jayne Murray, Chen Yang, Stefania Purgato, Cheng Fei Kong, Bing Liu, Michelle F. Maritz, Sieu L. Tran, and Rosemary O'Brien

Abstract

Text file of Figure Legends to Supplementary data

Published
2023
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44. Supplementary Figure 6 from MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin

Author

Karen L. MacKenzie, Jamie I. Fletcher, Giovanni Perini, Murray D. Norris, Preethi H. Gunaratne, Michelle Haber, Wendy B. London, Hilda A. Pickett, Georg von Jonquieres, Claudia L. Flemming, Amanda J. Russell, Jayne Murray, Chen Yang, Stefania Purgato, Cheng Fei Kong, Bing Liu, Michelle F. Maritz, Sieu L. Tran, and Rosemary O'Brien

Abstract

Supporting data; Supplementary Figure 6:Nucleolar dispersal of rpl5

Published
2023
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45. Single-Cell Sequencing Identifies Master Regulators Affected by Panobinostat in Neuroblastoma Cells

Author

Giorgio Milazzo, Giovanni Perini, Federico M. Giorgi, Milazzo G., Perini G., and Giorgi F.M.

Subjects
neuroblastoma, panobinostat, transcriptomics, master regulator analysi, Genetics, gene network, Kelly, gene networks, master regulator analysis, single-cell sequencing, Genetics (clinical)
Abstract

The molecular mechanisms and gene regulatory networks sustaining cell proliferation in neuroblastoma (NBL) cells are still not fully understood. In this tumor context, it has been proposed that anti-proliferative drugs, such as the pan-HDAC inhibitor panobinostat, could be tested to mitigate tumor progression. Here, we set out to investigate the effects of panobinostat treatment at the unprecedented resolution offered by single-cell sequencing. We identified a global senescence signature paired with reduction in proliferation in treated Kelly cells and more isolated transcriptional responses compatible with early neuronal differentiation. Using master regulator analysis, we identified BAZ1A, HCFC1, MAZ, and ZNF146 as the transcriptional regulators most significantly repressed by panobinostat. Experimental silencing of these transcription factors (TFs) confirmed their role in sustaining NBL cell proliferation in vitro.

Published
2022

47. Restoration of the molecular clock is tumor suppressive in neuroblastoma

Author

Nagireddy Putluri, Eveline Barbieri, John Hicks, Karthik reddy kami reddy, Pavel Sumazin, Thomas P. Burris, Simone Di Giacomo, Baharan Fekry, Ling Tao, Bokai Zhu, Mario Capasso, Giorgio Milazzo, Giovanni Perini, Sanjeev A. Vasudevan, Myrthala Moreno-Smith, Kristin Eckel-Mahan, Mahmoud A. Mohammad, Roshan Borkar, Moreno-Smith M., Milazzo G., Tao L., Fekry B., Zhu B., Mohammad M.A., Di Giacomo S., Borkar R., Reddy K.R.K., Capasso M., Vasudevan S.A., Sumazin P., Hicks J., Putluri N., Perini G., Eckel-Mahan K., Burris T.P., Barbieri E., Moreno-Smith, M., Milazzo, G., Tao, L., Fekry, B., Zhu, B., Mohammad, M. A., Di Giacomo, S., Borkar, R., Reddy, K. R. K., Capasso, M., Vasudevan, S. A., Sumazin, P., Hicks, J., Putluri, N., Perini, G., Eckel-Mahan, K., Burris, T. P., and Barbieri, E.

Subjects
0301 basic medicine, General Physics and Astronomy, Stimulation, Antineoplastic Agent, Mice, Neuroblastoma, 0302 clinical medicine, MYCN, Promoter Regions, Genetic, Cancer, N-Myc Proto-Oncogene Protein, Multidisciplinary, Chemistry, ARNTL Transcription Factors, Nuclear Receptor Subfamily 1, Group F, Member 1, ARNTL Transcription Factor, 030220 oncology & carcinogenesis, Benzamides, Lipogenesis, Human, Agonist, Cell biology, tumor, medicine.drug_class, Cell Survival, Science, Repressor, Antineoplastic Agents, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Benzamide, Cell Line, Tumor, medicine, Oscillation (cell signaling), Animals, Humans, neoplasms, Activator (genetics), Animal, Lipogenesi, Promoter, General Chemistry, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Cancer research, RNA-seq
Abstract

MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN., MYCN is frequently amplified in neuroblastomas. Here, the authors show that MYCN disrupts the molecular clock by downregulating clock activator RORα and that the reactivation of RORα restores BMAL1 activity, and inhibits lipid metabolism and neuroblastoma growth

Published
2021

48. PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis

Author

Heike Wollmann, David Papadopoli, Ravisankar Rajarethinam, Giovanni Perini, Michal Marek Hoppe, Laura Hulea, Soo Yong Tan, Emily Bernstein, Susan Swee Shan Hue, Choon Kiat Ong, Siok Bian Ng, Soon Thye Lim, Slim Mzoughi, Cheryl M. Koh, Ivan Topisirovic, Federico Di Tullio, Manikandan Lakshmanan, Corina Mihaela Motofeanu, Ernesto Guccione, Cheng Mun Wun, Oro Uchenunu, Chee Bing Ong, David Dominguez-Sola, Shun Xie Teo, Diana Low, Giuseppe Andreacchio, Gabriele Varano, Dachuan Huang, Muthafar Al-Haddawi, Paolo Pigini, Denis Torre, Y Peng, Anand D. Jeyasekharan, Julia N. Zhao, Philipp Kaldis, Jia Yi Fong, Matias J. Caldez, Keng Boon Wee, Dan Hasson, Mzoughi, Slim, Fong, Jia Yi, Papadopoli, David, Koh, Cheryl M, Hulea, Laura, Pigini, Paolo, Di Tullio, Federico, Andreacchio, Giuseppe, Hoppe, Michal Marek, Wollmann, Heike, Low, Diana, Caldez, Matias J, Peng, Yanfen, Torre, Deni, Zhao, Julia N, Uchenunu, Oro, Varano, Gabriele, Motofeanu, Corina-Mihaela, Lakshmanan, Manikandan, Teo, Shun Xie, Wun, Cheng Mun, Perini, Giovanni, Tan, Soo Yong, Ong, Chee Bing, Al-Haddawi, Muthafar, Rajarethinam, Ravisankar, Hue, Susan Swee-Shan, Lim, Soon Thye, Ong, Choon Kiat, Huang, Dachuan, Ng, Siok-Bian, Bernstein, Emily, Hasson, Dan, Wee, Keng Boon, Kaldis, Philipp, Jeyasekharan, Anand, Dominguez-Sola, David, Topisirovic, Ivan, and Guccione, Ernesto

Subjects
0301 basic medicine, Lymphoma, Transcription Factor, Somatic cell, Regulator, General Physics and Astronomy, Apoptosis, Mice, SCID, Mice, Phosphatidylinositol 3-Kinases, Random Allocation, 0302 clinical medicine, lcsh:Science, Multidisciplinary, B-cell lymphoma, Flow Cytometry, Cell biology, DNA-Binding Proteins, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Human, Chromatin Immunoprecipitation, Cell Survival, DNA-Binding Protein, Science, Blotting, Western, Biology, Article, General Biochemistry, Genetics and Molecular Biology, NO, 03 medical and health sciences, medicine, Animals, Humans, Transcriptomics, Gene, Protein kinase B, PI3K/AKT/mTOR pathway, B cell, Animal, Apoptosi, Computational Biology, General Chemistry, medicine.disease, 030104 developmental biology, Gene Expression Regulation, lcsh:Q, Phosphatidylinositol 3-Kinase, Transcriptome, Chromatin immunoprecipitation, Transcription Factors
Abstract

PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology., The transcriptional regulator PRDM15 is expressed at low levels in normal tissues but overexpressed in B-cell lymphomas. Here, the authors show that PRDM15 depletion does not affect adult somatic cell homeostasis but leads to a metabolic crisis which impairs B-cell lymphomagenesis.

Published
2020
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49. Comparing 1-year effectiveness and acceptability of once-monthly paliperidone palmitate and aripiprazole monohydrate for schizophrenia spectrum disorders: Findings from the STAR Network Depot Study

Author

Francesco Bartoli, A, Daniele Cavaleri, A, Tommaso Callovini, A, Ilaria Riboldi, A, Cristina Crocamo, A, Armando D’Agostino, B, Giovanni Martinotti, C, Federico Bertolini, D, Giovanni Ostuzzi, D, Corrado Barbui, D, Giuseppe Carr`a, A, STAR Network Depot Investigators, Corrado, Barbui, Federico, Bertolini, Filippo, Boschello, Chiara, Gastaldon, Maria Angela Mazzi, Michela, Nos´e, Giovanni, Ostuzzi, Davide, Papola, Giovanni, Perini, Alberto, Piccoli, Michela, Pievani, Marianna, Purgato, Mirella, Ruggeri, Federico, Tedeschi, Samira, Terlizzi, and Giulia Turrini (Verona), Mariarita, Caroleo, Pasquale De Fazio, Fabio, Magliocco, and Gaetano Raffaele (Catanzaro), Simone, Cavallotti, Margherita, Chirico, Armando, D’Agostino, Farida, Ferrato, Ivan, Limosani, Daniele, Mastromo, Emiliano, Monzani, Edoardo Giuseppe Ostinelli, Matteo, Porcellana, and Francesco Restaino (Milano), Pasqua Maria Annese, Simone, Bolognesi, Massimiliano, Cerretini, Alberto De Capua, Sara, Debolini, Maria Del Zanna, Francesco, Fargnoli, Alessandra, Giannini, Livia, Luccarelli, Claudio, Lucii, Elisa, Pierantozzi, and Fiorella Tozzi (Siena), Francesco, Bardicchia, Giuseppe, Cardamone, Edvige, Facchi, Nadia, Magnani, and Federica Soscia (Grosseto), Bruno Biancosino, and Spyridon Zotos (Ferrara), Marzio, Giacomin, Francesco, Pompei, Mariangela, Spano, and Filippo Zonta (Treviso), Buzzi, ALDO EMANUELE, Callegari, Camilla, Roberta, Calzolari, Caselli, Ivano, Marcello, Diurni, Edoardo Luigi Giana, Ielmini, Marta, Anna, Milano, Emanuele, Sani, and Daniele Zizolfi (Varese), Gabrio, Alberini, Paola, Bortolaso, Sara, Cazzamalli, Chiara, Costantini, Angela Di Caro, Chiara, Paronelli, Silvia, Piantanida, and Marco Piccinelli (Varese Verbano), Papalini, Alessandro, Silva Veronica Barbanti, Chiara, D’Ippolito, Mauro, Gozzi, and Valentina Moretti (Reggio Emilia), Ornella, Campese, Mariangela, Corbo, Lucia Di Capro, Massimo di Giannantonio, Federica, Fiori, Marco, Lorusso, Valerio, Mancini, Giovanni, Martinotti, and Daniela Viceconte (Chieti), Carmela, Calandra, Maria, Luca, Maria Salvina Signorelli, and Francesco Suraniti (Catania), Beatrice, Balzarro, Giancarlo, Boncompagni, Valentina, Caretto, Roberta, Emiliani, Pasqualino, Lupoli, Marco, Menchetti, Eugenio, Rossi, Viviana, Storbini, Ilaria, Tarricone, and Laura Terzi (Bologna), Marianna, Boso, Cristina, Catania, Giuseppe De Paoli, and Paolo Risaro (Pavia), Flora, Aspesi, Francesco, Bartoli, Mattia, Bava, Adele, Bono, Giulia, Brambilla, Giuseppe, Carr`a, Gloria, Castagna, Sara, Lucchi, Roberto, Nava, Milena, Provenzi, Tommaso, Tabacchi, Martina, Tremolada, and Enrica Verrengia (Monza), Michela Barchiesi and Maria Ginevra Oriani (Ancona), Monica Pacetti (Forlì), Andrea, Aguglia, Maurizio, Ferro, and Lucio Ghio (Genova), Rossella, Beneduce, Laura, Laffranchini, Laura Rosa Magni, Giuseppe, Rossi, and Giovanni Battista Tura (Brescia), Lelio, Addeo, Giovanni, Balletta, Elisa De Vivo, Rossella Di Benedetto, and Vincenzo Fricchione Parise (Avellino), Bernardo Carpiniello and Federica Pinna (Cagliari), Damiano Pecile (Mantova), Chiara Mattei (Fermo), Tommaso, Bonavigo, Elisabetta Pascolo Fabrici, Sofia, Panarello, Giulia, Peresson, and Claudio Vitucci (Trieste), Francesco Gardellin, and Stefania Strizzolo (Vicenza), Edoardo, Cossetta, Carlo, Fizzotti, and Daniele Moretti (Savona), Luana Di Gregorio and Francesca Sozzi (Trento), Giuseppe Colli and Daniele La Barbera (Palermo), and Sabrina Laurenzi (Civitanova, Marche)., Bartoli, F, Cavaleri, D, Callovini, T, Riboldi, I, Crocamo, C, D'Agostino, A, Martinotti, G, Bertolini, F, Ostuzzi, G, Barbui, C, Carra, G, and Bartoli, F., Cavaleri, D., Callovini, T., Riboldi, I., Crocamo, C., D'Agostino, A., Martinotti, G., Bertolini, F., Ostuzzi, G., Barbui, C., Carrà, G., Boschello, F., Gastaldon, C., Mazzi, M.A., Nosé, M., Papola, D., Perini, G., Piccoli, A., Pievani, M., Purgato, M., Ruggeri, M., Tedeschi, F., Terlizzi, S., Turrini, G., Caroleo, M., De Fazio, P., Magliocco, F., Raffaele, G., Chirico, M., Ferrato, F., Limosani, I., Mastromo, D., Monzani, E., Ostinelli, E.G., Porcellana, M., Restaino, F., Annese, P.M., Bolognesi, S., Cerretini, M., De Capua, A., Debolini, S., Del Zanna, M., Fargnoli, F., Giannini, A., Luccarelli, L., Lucii, C., Pierantozzi, E., Tozzi, F., Bardicchia, F., Cardamone, G., Facchi, E., Magnani, N., Soscia, F., Biancosino, B., Zotos, S., Giacomin, M., Pompei, F., Spano, M., Zonta, F., Buzzi, A., Callegari, C., Calzolari, R., Caselli, I., Diurni, M., Giana, E.L., Ielmini, M., Milano, A., Poloni, N., Sani, E., Zizolfi, D., Alberini, G., Bortolaso, P., Cazzamalli, S., Costantini, C., Di Caro, A., Paronelli, C., Piantanida, S., Piccinelli, M., Alessandro, P., Barbanti, S.V., D'Ippolito, C., Gozzi, M., Moretti, V., Corbo, M., Di Capro, L., di Giannantonio, M., Fiori, F., Lorusso, M., Mancini, V., Viceconte, D., Calandra, C., Luca, M., Signorelli, M.S., Suraniti, F., Balzarro, B., Boncompagni, G., Caretto, V., Emiliani, R., Lupoli, P., Menchetti, M., Rossi, E., Storbini, V., Tarricone, I., Terzi, L., Boso, M., Catania, C., De Paoli, G., Risaro, P., Aspesi, F., Bava, M., Bono, A., Brambilla, G., Castagna, G., Lucchi, S., Nava, R., Provenzi, M., Tabacchi, T., Tremolada, M., Verrengia, E., Barchiesi, M., Oriani, M.G., Aguglia, A., Ferro, M., Ghio, L., Beneduce, R., Laffranchini, L., Magni, L.R., Rossi, G., Tura, G.B., Addeo, L., Balletta, G., De Vivo, E., Di Benedetto, R., Parise, V.F., Carpiniello, B., Pinna, F., Pecile, D., Mattei, C., Bonavigo, T., Fabrici, E.P., Panarello, S., Peresson, G., Vitucci, C., Pacetti, M., Gardellin, F., Strizzolo, S., Cossetta, E., Fizzotti, C., Moretti, D., Di Gregorio, L., Sozzi, F., Colli, G., La Barbera, D., Laurenzi, S.

Subjects
Long-acting injectable antipsychotic, Paliperidone palmitate 1-month, Aripiprazole, Aripiprazole monohydrate, Long-acting injectable antipsychotics, Psychiatry and Mental health, Paliperidone Palmitate, Schizophrenia, Humans, Prospective Studies, Settore MED/25 - Psichiatria, Biological Psychiatry, Antipsychotic Agents
Abstract

In this prospective study, we assessed the effectiveness and acceptability of paliperidone palmitate 1-month (PP1M) and aripiprazole monohydrate (AM) over 1-year follow-up. We included 195 subjects (117 treated with PP1M and 78 with AM) with schizophrenia spectrum disorders from real-world settings. We estimated no differences in hospitalization (Odds Ratio=1.59; p = 0.12), symptoms improvement (p = 0.90 adjusted for baseline severity), and discontinuation (Hazard Ratio=0.72; p = 0.20) at study endpoint. Although current evidence suggests the possible superiority of AM over PP1M, our findings showed comparable effectiveness between these drugs. Additional studies in real-world settings with direct comparisons between these two LAIs are needed.

Published
2022

50. Bipolar spectrum symptoms in patients with fibromyalgia: a dimensional psychometric evaluation of 120 patients

Author

Vittorio Schweiger, Giovanni Perini, Lidia Del Piccolo, Cinzia Perlini, Valeria Donisi, Leonardo Gottin, Alvise Martini, Katia Donadello, Giovanna Del Balzo, Valentina Moro, Erica Secchettin, and Enrico Polati

Subjects
bipolar spectrum, depressive symptoms, Health, Toxicology and Mutagenesis, Public Health, Environmental and Occupational Health, manic symptoms, fibromyalgia, chronic pain
Abstract

Background: Fibromyalgia Syndrome (FMS) is characterized by chronic widespread pain, fatigue, unrefreshing sleep and cognitive dysfunction. Depressive and manic symptoms are often reported in FMS patients’ history. The aim of this study was to evaluate the prevalence of bipolar spectrum symptoms (BSS) and to correlate these with quality of life (QoL) scores and antidepressant treatment. Methods: From October 2017 to July 2018, a battery of QoL questionnaires (FIQ, PSQI and SF-12) was administered to 120 FMS patients after a clinical examination. The MOODS-SR lifetime questionnaire was then remotely administered to the patients included in the study. Results: The presence of depressive and manic lifetime symptoms was found, in line with the results of the available literature. A correlation was found between the history of depressive symptoms and the severity of FIQ and SF-12 scores. Despite a low statistical strength, a trend toward a correlation between a history of manic symptoms and SNRI treatment was detected. Conclusions: The correlation between the MOOD—depressive domains and poor QoL is in line with the available literature. Further studies are needed to corroborate these findings and to elucidate the relationship between manic symptoms and SNRI treatment.

Published
2022

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