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Elli Papaemmanuil

Luca Malcovati, Anna Gallì, Erica Travaglino, Ilaria Ambaglio, Ettore Rizzo, Elisabetta Molteni, Chiara Elena, Virginia Valeria Ferretti, Silvia Catricalà, Elisa Bono, Gabriele Todisco, Antonio Bianchessi, Elisa Rumi, Silvia Zibellini, Daniela Pietra, Emanuela Boveri, Clara Camaschella, Daniela Toniolo, Elli Papaemmanuil, Seishi Ogawa, Mario Cazzola
Unexplained blood cytopenias, in particular anemia, are often found in older persons. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. We studied a prospective cohort of patients with unexplained cytopenia with the aim to estimate the predictive value of somatic mutations for identifying subjects with, or at risk of developing a myeloid neoplasm. The study included a learning cohort of 683 consecutive patients investigated for unexplained cytopenia, and a validation cohort of 190 patients referred for suspected myeloid neoplasm...
April 19, 2017: Blood
Andriana G Kotini, Chan-Jung Chang, Arthur Chow, Han Yuan, Tzu-Chieh Ho, Tiansu Wang, Shailee Vora, Alexander Solovyov, Chrystel Husser, Malgorzata Olszewska, Julie Teruya-Feldstein, Deepak Perumal, Virginia M Klimek, Alexandros Spyridonidis, Raajit K Rampal, Lewis Silverman, E Premkumar Reddy, Elli Papaemmanuil, Samir Parekh, Benjamin D Greenbaum, Christina S Leslie, Michael G Kharas, Eirini P Papapetrou
Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia...
March 2, 2017: Cell Stem Cell
Moritz Gerstung, Elli Papaemmanuil, Inigo Martincorena, Lars Bullinger, Verena I Gaidzik, Peter Paschka, Michael Heuser, Felicitas Thol, Niccolo Bolli, Peter Ganly, Arnold Ganser, Ultan McDermott, Konstanze Döhner, Richard F Schlenk, Hartmut Döhner, Peter J Campbell
Underpinning the vision of precision medicine is the concept that causative mutations in a patient's cancer drive its biology and, by extension, its clinical features and treatment response. However, considerable between-patient heterogeneity in driver mutations complicates evidence-based personalization of cancer care. Here, by reanalyzing data from 1,540 patients with acute myeloid leukemia (AML), we explore how large knowledge banks of matched genomic-clinical data can support clinical decision-making. Inclusive, multistage statistical models accurately predicted likelihoods of remission, relapse and mortality, which were validated using data from independent patients in The Cancer Genome Atlas...
March 2017: Nature Genetics
Lisa J Russell, Lisa Jones, Amir Enshaei, Stefano Tonin, Sarra L Ryan, Jeyanthy Eswaran, Sirintra Nakjang, Elli Papaemmanuil, Jose M C Tubio, Adele K Fielding, Ajay Vora, Peter J Campbell, Anthony V Moorman, Christine J Harrison
Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We aimed to determine the clinical and genetic landscape of those with IGH-CRLF2 or P2RY8-CRLF2 (CRLF2-r) using multiple genomic approaches. Clinical and demographic features of CRLF2-r patients were characteristic of B-ALL. Patients with IGH-CRLF2 were older (14 y vs. 4 y, P < .001), while the incidence of CRLF2-r among Down syndrome patients was high (50/161, 31%)...
May 2017: Genes, Chromosomes & Cancer
Marios Dimitriou, Petter S Woll, Teresa Mortera-Blanco, Mohsen Karimi, David C Wedge, Helen Doolittle, Iyadh Douagi, Elli Papaemmanuil, Sten Eirik W Jacobsen, Eva Hellström-Lindberg
The stem and progenitor cell compartments in low- and intermediate-risk myelodysplastic syndromes (MDS) have recently been described, and shown to be highly conserved when compared to those in acute myeloid leukemia (AML). Much less is known about the characteristics of the hematopoietic hierarchy of subgroups of MDS with a high risk of transforming to AML. Immunophenotypic analysis of immature stem and progenitor cell compartments from patients with an isolated loss of the entire chromosome 7 (isolated -7), an independent high-risk genetic event in MDS, showed expansion and dominance of the malignant -7 clone in the granulocyte and macrophage progenitors (GMP), and other CD45RA+ progenitor compartments, and a significant reduction of the LIN-CD34+CD38low/-CD90+CD45RA- hematopoietic stem cell (HSC) compartment, highly reminiscent of what is typically seen in AML, and distinct from low-risk MDS...
November 8, 2016: Oncotarget
Matteo G Della Porta, Anna Gallì, Andrea Bacigalupo, Silvia Zibellini, Massimo Bernardi, Ettore Rizzo, Bernardino Allione, Maria Teresa van Lint, Pietro Pioltelli, Paola Marenco, Alberto Bosi, Maria Teresa Voso, Simona Sica, Mariella Cuzzola, Emanuele Angelucci, Marianna Rossi, Marta Ubezio, Alberto Malovini, Ivan Limongelli, Virginia V Ferretti, Orietta Spinelli, Cristina Tresoldi, Sarah Pozzi, Silvia Luchetti, Laura Pezzetti, Silvia Catricalà, Chiara Milanesi, Alberto Riva, Benedetto Bruno, Fabio Ciceri, Francesca Bonifazi, Riccardo Bellazzi, Elli Papaemmanuil, Armando Santoro, Emilio P Alessandrino, Alessandro Rambaldi, Mario Cazzola
PURPOSE: The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. PATIENTS AND METHODS: We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms...
September 6, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Adam Shlien, Keiran Raine, Fabio Fuligni, Roland Arnold, Serena Nik-Zainal, Serge Dronov, Lira Mamanova, Andrej Rosic, Young Seok Ju, Susanna L Cooke, Manasa Ramakrishna, Elli Papaemmanuil, Helen R Davies, Patrick S Tarpey, Peter Van Loo, David C Wedge, David R Jones, Sancha Martin, John Marshall, Elizabeth Anderson, Claire Hardy, Violetta Barbashina, Samuel A J R Aparicio, Torill Sauer, Øystein Garred, Anne Vincent-Salomon, Odette Mariani, Sandrine Boyault, Aquila Fatima, Anita Langerød, Åke Borg, Gilles Thomas, Andrea L Richardson, Anne-Lise Børresen-Dale, Kornelia Polyak, Michael R Stratton, Peter J Campbell
Disordered transcriptomes of cancer encompass direct effects of somatic mutation on transcription, coordinated secondary pathway alterations, and increased transcriptional noise. To catalog the rules governing how somatic mutation exerts direct transcriptional effects, we developed an exhaustive pipeline for analyzing RNA sequencing data, which we integrated with whole genomes from 23 breast cancers. Using X-inactivation analyses, we found that cancer cells are more transcriptionally active than intermixed stromal cells...
August 16, 2016: Cell Reports
Elli Papaemmanuil, Moritz Gerstung, Lars Bullinger, Verena I Gaidzik, Peter Paschka, Nicola D Roberts, Nicola E Potter, Michael Heuser, Felicitas Thol, Niccolo Bolli, Gunes Gundem, Peter Van Loo, Inigo Martincorena, Peter Ganly, Laura Mudie, Stuart McLaren, Sarah O'Meara, Keiran Raine, David R Jones, Jon W Teague, Adam P Butler, Mel F Greaves, Arnold Ganser, Konstanze Döhner, Richard F Schlenk, Hartmut Döhner, Peter J Campbell
BACKGROUND: Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. METHODS: We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes...
June 9, 2016: New England Journal of Medicine
Young Seok Ju, Jose M C Tubio, William Mifsud, Beiyuan Fu, Helen R Davies, Manasa Ramakrishna, Yilong Li, Lucy Yates, Gunes Gundem, Patrick S Tarpey, Sam Behjati, Elli Papaemmanuil, Sancha Martin, Anthony Fullam, Moritz Gerstung, Jyoti Nangalia, Anthony R Green, Carlos Caldas, Åke Borg, Andrew Tutt, Ming Ta Michael Lee, Laura J Van't Veer, Benita K T Tan, Samuel Aparicio, Paul N Span, John W M Martens, Stian Knappskog, Anne Vincent-Salomon, Anne-Lise Børresen-Dale, Jórunn Erla Eyfjörd, Ola Myklebost, Adrienne M Flanagan, Christopher Foster, David E Neal, Colin Cooper, Rosalind Eeles, G Steven Bova, Sunil R Lakhani, Christine Desmedt, Gilles Thomas, Andrea L Richardson, Colin A Purdie, Alastair M Thompson, Ultan McDermott, Fengtang Yang, Serena Nik-Zainal, Peter J Campbell, Michael R Stratton
No abstract text is available yet for this article.
May 2016: Genome Research
Francesca Mastaglio, Khaled Bedair, Elli Papaemmanuil, Michael J Groves, Ann Hyslop, Norene Keenan, Eleanor J Hothersall, Peter J Campbell, David T Bowen, Sudhir Tauro
Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest). Clinicopathological features and outcomes between SES quintiles containing 15%, 20%, 19%, 30% and 16% of patients were compared...
July 2016: British Journal of Haematology
Lacramioara Botezatu, Lars C Michel, Hideki Makishima, Thomas Schroeder, Ulrich Germing, Rainer Haas, Bert van der Reijden, Anne E Marneth, Saskia M Bergevoet, Joop H Jansen, Bartlomiej Przychodzen, Marcin Wlodarski, Charlotte Niemeyer, Uwe Platzbecker, Gerhard Ehninger, Ashwin Unnikrishnan, Dominik Beck, John Pimanda, Eva Hellström-Lindberg, Luca Malcovati, Jacqueline Boultwood, Andrea Pellagatti, Elli Papaemmanuil, Philipp Le Coutre, Jaspal Kaeda, Bertram Opalka, Tarik Möröy, Ulrich Dührsen, Jaroslaw Maciejewski, Cyrus Khandanpour
Inherited gene variants play an important role in malignant diseases. The transcriptional repressor growth factor independence 1 (GFI1) regulates hematopoietic stem cell (HSC) self-renewal and differentiation. A single-nucleotide polymorphism of GFI1 (rs34631763) generates a protein with an asparagine (N) instead of a serine (S) at position 36 (GFI1(36N)) and has a prevalence of 3%-5% among Caucasians. Because GFI1 regulates myeloid development, we examined the role of GFI1(36N) on the course of MDS disease...
July 2016: Experimental Hematology
Simona Conte, Shintaro Katayama, Liselotte Vesterlund, Mohsen Karimi, Marios Dimitriou, Monika Jansson, Teresa Mortera-Blanco, Per Unneberg, Elli Papaemmanuil, Birgitta Sander, Tiina Skoog, Peter Campbell, Julian Walfridsson, Juha Kere, Eva Hellström-Lindberg
Refractory anaemia with ring sideroblasts (RARS) is distinguished by hyperplastic inefficient erythropoiesis, aberrant mitochondrial ferritin accumulation and anaemia. Heterozygous mutations in the spliceosome gene SF3B1 are found in a majority of RARS cases. To explore the link between SF3B1 mutations and anaemia, we studied mutated RARS CD34(+) marrow cells with regard to transcriptome sequencing, splice patterns and mutational allele burden during erythroid differentiation. Transcriptome profiling during early erythroid differentiation revealed a marked up-regulation of genes involved in haemoglobin synthesis and in the oxidative phosphorylation process, and down-regulation of mitochondrial ABC transporters compared to normal bone marrow...
November 2015: British Journal of Haematology
Srividya Swaminathan, Lars Klemm, Eugene Park, Elli Papaemmanuil, Anthony Ford, Soo-Mi Kweon, Daniel Trageser, Brian Hasselfeld, Nadine Henke, Jana Mooster, Huimin Geng, Klaus Schwarz, Scott C Kogan, Rafael Casellas, David G Schatz, Michael R Lieber, Mel F Greaves, Markus Müschen
Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes...
July 2015: Nature Immunology
Young Seok Ju, Jose M C Tubio, William Mifsud, Beiyuan Fu, Helen R Davies, Manasa Ramakrishna, Yilong Li, Lucy Yates, Gunes Gundem, Patrick S Tarpey, Sam Behjati, Elli Papaemmanuil, Sancha Martin, Anthony Fullam, Moritz Gerstung, Jyoti Nangalia, Anthony R Green, Carlos Caldas, Åke Borg, Andrew Tutt, Ming Ta Michael Lee, Laura J van't Veer, Benita K T Tan, Samuel Aparicio, Paul N Span, John W M Martens, Stian Knappskog, Anne Vincent-Salomon, Anne-Lise Børresen-Dale, Jórunn Erla Eyfjörd, Ola Myklebost, Adrienne M Flanagan, Christopher Foster, David E Neal, Colin Cooper, Rosalind Eeles, Steven G Bova, Sunil R Lakhani, Christine Desmedt, Gilles Thomas, Andrea L Richardson, Colin A Purdie, Alastair M Thompson, Ultan McDermott, Fengtang Yang, Serena Nik-Zainal, Peter J Campbell, Michael R Stratton
Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved...
June 2015: Genome Research
Luca Malcovati, Mohsen Karimi, Elli Papaemmanuil, Ilaria Ambaglio, Martin Jädersten, Monika Jansson, Chiara Elena, Anna Gallì, Gunilla Walldin, Matteo G Della Porta, Klas Raaschou-Jensen, Erica Travaglino, Klaus Kallenbach, Daniela Pietra, Viktor Ljungström, Simona Conte, Emanuela Boveri, Rosangela Invernizzi, Richard Rosenquist, Peter J Campbell, Mario Cazzola, Eva Hellström Lindberg
Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts...
July 9, 2015: Blood
Gunes Gundem, Peter Van Loo, Barbara Kremeyer, Ludmil B Alexandrov, Jose M C Tubio, Elli Papaemmanuil, Daniel S Brewer, Heini M L Kallio, Gunilla Högnäs, Matti Annala, Kati Kivinummi, Victoria Goody, Calli Latimer, Sarah O'Meara, Kevin J Dawson, William Isaacs, Michael R Emmert-Buck, Matti Nykter, Christopher Foster, Zsofia Kote-Jarai, Douglas Easton, Hayley C Whitaker, David E Neal, Colin S Cooper, Rosalind A Eeles, Tapio Visakorpi, Peter J Campbell, Ultan McDermott, David C Wedge, G Steven Bova
Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones...
April 16, 2015: Nature
Christina A Ortmann, David G Kent, Jyoti Nangalia, Yvonne Silber, David C Wedge, Jacob Grinfeld, E Joanna Baxter, Charles E Massie, Elli Papaemmanuil, Suraj Menon, Anna L Godfrey, Danai Dimitropoulou, Paola Guglielmelli, Beatriz Bellosillo, Carles Besses, Konstanze Döhner, Claire N Harrison, George S Vassiliou, Alessandro Vannucchi, Peter J Campbell, Anthony R Green
BACKGROUND: Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. METHODS: We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells...
February 12, 2015: New England Journal of Medicine
Moritz Gerstung, Andrea Pellagatti, Luca Malcovati, Aristoteles Giagounidis, Matteo G Della Porta, Martin Jädersten, Hamid Dolatshad, Amit Verma, Nicholas C P Cross, Paresh Vyas, Sally Killick, Eva Hellström-Lindberg, Mario Cazzola, Elli Papaemmanuil, Peter J Campbell, Jacqueline Boultwood
Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20-65% of observed expression variability...
January 9, 2015: Nature Communications
Niccolò Bolli, Nicla Manes, Thomas McKerrell, Jianxiang Chi, Naomi Park, Gunes Gundem, Michael A Quail, Vijitha Sathiaseelan, Bram Herman, Charles Crawley, Jenny I O Craig, Natalie Conte, Carolyn Grove, Elli Papaemmanuil, Peter J Campbell, Ignacio Varela, Paul Costeas, George S Vassiliou
Prognostic stratification is critical for making therapeutic decisions and maximizing survival of patients with acute myeloid leukemia. Advances in the genomics of acute myeloid leukemia have identified several recurrent gene mutations whose prognostic impact is being deciphered. We used HaloPlex target enrichment and Illumina-based next generation sequencing to study 24 recurrently mutated genes in 42 samples of acute myeloid leukemia with a normal karyotype. Read depth varied between and within genes for the same sample, but was predictable and highly consistent across samples...
February 2015: Haematologica
Carlo B Gambacorti-Passerini, Carla Donadoni, Andrea Parmiani, Alessandra Pirola, Sara Redaelli, Giovanni Signore, Vincenzo Piazza, Luca Malcovati, Diletta Fontana, Roberta Spinelli, Vera Magistroni, Giuseppe Gaipa, Marco Peronaci, Alessandro Morotti, Cristina Panuzzo, Giuseppe Saglio, Emilio Usala, Dong-Wook Kim, Delphine Rea, Konstantinos Zervakis, Nora Viniou, Argiris Symeonidis, Heiko Becker, Jacqueline Boultwood, Leonardo Campiotti, Matteo Carrabba, Elena Elli, Graham R Bignell, Elli Papaemmanuil, Peter J Campbell, Mario Cazzola, Rocco Piazza
Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2...
January 15, 2015: Blood
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