St. Anna Children s Cancer Research Institute 25 Years. Science Report St. Anna Kinderkrebsforschung 25 Jahre. Forschungsbericht

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1 St. Anna Children s Cancer Research Institute 25 Years. Science Report St. Anna Kinderkrebsforschung 25 Jahre. Forschungsbericht

2 St. Anna Children s Cancer Research Institute 25 Years. Science Report St. Anna Kinderkrebsforschung 25 Jahre. Forschungsbericht

3 Quotes by Helmut Gadner Extracts from past Science Reports 25 Years / 25 Jahre A Brief Review Ein kurzer Rückblick Extracts from past CCRI Science Reports Auszüge aus vergangenen Jahresberichten der St. Anna Kinderkrebsforschung Helmut Gadner, Director of the Institute: Quotes from an Interview in October 2012 Helmut Gadner, Institutsleiter: Zitate aus einem Interview im Oktober 2012 Time Travel through Iconic Images Eine Zeitreise in Bildern

4 Quotes by Helmut Gadner Extracts from past Science Reports Quotes by Helmut Gadner Extracts from past Science Reports 25 Years / 25 Jahre Among all types of malignant childhood cancer we had to deal with, leukaemia was certainly the biggest challenge. Leukämie war unter den bösartigen Erkrankungen im Kindes- und Jugendalter damals diejenige, wo es den größten Handlungsbedarf gab. After successful implementation of a novel treatment concept for children with cancer, I knew that we would need to see further progress. Being the Medical Director of the St. Anna Children s Hospital, in 1985, I realised that all our therapeutic possibilities seemed to have hit the end of the road. Nach erfolgreicher Einführung eines neuen Behandlungskonzeptes für krebskranke Kinder habe ich als ärztlicher Direktor des St. Anna Kinderspitals im Jahr 1985 gewusst, dass wir noch mehr tun müssen, um weiter zu kommen. Die therapeutischen Möglichkeiten führten in eine Sackgasse. Thanks to the continuous financial support of our donors and various funds, it was possible to establish seven different research groups in the five labs that were available. Dank anhaltendem Spendenfluss und Unterstützung durch diverse Fonds war es möglich, in den fünf zur Verfügung stehenden Labors sieben Arbeitsgruppen zu beschäftigen. (Science Report 1990) After only one year of construction time, and financed exclusively by private donations, the Children s Cancer Research Institute went operational in June Das Forschungsinstitut für krebskranke Kinder wurde im Juni 1988 nach einer einjährigen Bauzeit, deren Kosten ausschließlich aus Spenden der Öffentlichkeit getragen worden sind, seiner Bestimmung übergeben. (Science Report 1989)

5 Quotes by Helmut Gadner Extracts from past Science Reports Quotes by Helmut Gadner Extracts from past Science Reports 25 Years / 25 Jahre In some areas, discoveries made at the CCRI have already been translated into new treatment strategies. In einzelnen Bereichen ist es gelungen, Erkenntnisse, die im Forschungsinstitut gewonnen wurden, in die Etablierung neuer Behandlungsstrategien umzusetzen. (Science Report 1994) The close cooperation of clinicians and researchers proves to be extremely beneficial to the patients. Die enge Zusammenarbeit von Klinikern und Forschern, wenn es um Belange des Patienten geht, hat sich hervorragend bewährt. (Science Report 1995/96) The primary goal of the newly founded institute was the improvement of diagnostics using novel technologies. In addition, we wanted to establish basic research and conduct clinical trials. Our expectations were exceeded in every respect. Die wichtigste Aufgabe des neu gegründeten Forschungsinstituts war die verbesserte Diagnostik mittels neuer Technologien. Zudem wollten wir auch die Grundlagenforschung etablieren und klinische Studien durchführen. Diese Ziele wurden bereits in wenigen Jahren mehr als übertroffen. In 1992 the CCRI s company profile changed: applied research, sophisticated diagnostics, and basic research are now equally important. Im Jahr 1992 vertiefte sich das für das Forschungsinstitut charakteristische Profil: angewandte Forschung, verfeinerte Diagnostik und Grundlagenforschung stehen gleichberechtigt nebeneinander. (Science Report 1992)

6 Quotes by Helmut Gadner Extracts from past Science Reports Quotes by Helmut Gadner Extracts from past Science Reports 25 Years / 25 Jahre...the research activities of the CCRI are based partly on the work of diploma and PhD students from different disciplines Thus we perform an important role in the training of future researchers so baut die wissenschaftliche Arbeit zu einem guten Teil auf der Mitarbeit und dem Einsatz von Studenten aus verschiedenen Disziplinen auf... Damit übernimmt das Forschungsinstitut auch eine große Aufgabe in der Ausbildung dieser angehenden Wissenschafter... (Science Report 2000/01)...the fast development in haemato-oncology, which was observed in the last decade world-wide, led to a further diversification of the questions in this field also in our Institute...the transfer of examinations, which have in the meantime become routine examinations, to an especially equipped laboratory weltweit beobachtete rasante Entwicklung auf dem Gebiet der Hämato-Onkologie hat auch in unserem Institut dazu geführt, dass eine weitere Diversifizierung der Fragestellungen aufgetreten ist Auslagerung von inzwischen in Routine übergangenen Untersuchungen in ein speziell dafür eingerichtetes Labor... (Science Report 1998/99)

7 Quotes by Helmut Gadner Extracts from past Science Reports Quotes by Helmut Gadner Extracts from past Science Reports 25 Years / 25 Jahre Enduring commitment of each individual research group builds the institute s mission statement. The steadily increasing number of external grants makes the visions of CCRI scientists become reality. Das Engagement der einzelnen Forschungsgruppen ist heute das Leitbild des Instituts. Die zunehmenden Erfolge in der Einwerbung von Drittmitteln zeigen, dass man hier am CCRI sehr bemüht ist eigene Visionen zu realisieren. Good networking and international collaborations are still essential to make the best therapies available to young cancer patients. Gute Vernetzung sowie nationale und internationale Zusammenarbeit sind nach wie vor essentiell, um die Forschung weiter voran zu treiben und jungen Krebspatienten die beste Therapie zu ermöglichen....it was possible to raise the contribution of external competitive grants to the research budget to 38%, which in part was due to the successful participation in national...and international...cluster projects...as a result, it was possible to initiate in-house bioinformatic support... konnte der Anteil extern finanzierter Projektmittel auf 38% gehoben werden was zu einem guten Teil auf die Teilnahme an nationalen und internationalen Kooperationsprojekten zurückzuführen ist... in der Folge die Bioinformatik als Unterstützung im eigenen Haus zu etablieren... (Science Report 2006/07/08)

8 Quotes by Helmut Gadner Extracts from past Science Reports Quotes by Helmut Gadner Extracts from past Science Reports 25 Years / 25 Jahre Zukunftsweisend sind personalisierte Therapien sowie Genomanalysen, die uns Einblicke in die Ursachen einer bestimmten Krebserkrankung ermöglichen. In the future, genome analyses will enable us to further personalise therapies and reveal the mechanisms of cancer development and progression. Reflections on the past 25 years of children s cancer research point to a promising future: There are many open questions that still need to be answered. Die Rückschau auf 25 Jahre Kinderkrebsforschung lässt uns hoffnungsvoll in die Zukunft blicken: Es sind noch so viele Fragen offen....in January 2009 we were able to relocate our research laboratories into the newly-constructed institutional building...it also opened up new paths as regards translational and applied research...more third-party funding than in previous years...networks enabled our researchers to gain access to very expensive genomic and post-genomic high-throughput technology Im Jänner 2009 konnten die Forschungslabors in das neu errichtete Institutsgebäude übersiedeln... dies eröffnet neue Wege in der translatorischen und angewandten Forschung... mehr Drittmittelgelder als in den Jahren zuvor... Zugang zu sehr teuren genomischen und postgenomischen Hochdurchsatz-Technologien... My wish is that this institute can sustain its outstanding reputation by keeping up with novel developments and expanding its research efforts. Ich wünsche mir, dass das Institut auch in Zukunft mit dem starken Aufwärtstrend der letzte Jahre Schritt halten kann und die Forschung hier so weiter besteht wie bisher. (Science Report 2009/10)

9 3 25 Years Children s Cancer Research Institute A Brief Review 16 Preface Research Report Leukaemias 20 Immunological Diagnostics Michael N. Dworzak 24 Biology of Leukaemias Renate Panzer-Grümayer 30 Genetics of Leukaemia Sabine Strehl Solid Tumours 36 Tumour Biology Peter F. Ambros 42 Molecular Biology of Solid Tumours Heinrich Kovar Immunology 48 Tumour Immunology Thomas Felzmann 54 Clinical Cell Biology and FACS Core Unit Gerhard Fritsch 60 Transplantation-Immunology Andreas Heitger 66 Development of Cellular Therapeutics Wolfgang Holter 72 Molecular Microbiology and Labdia Labordiagnostik GmbH Thomas Lion 80 Clinical Research S 2 IRP, Studies & Statistics of Integrated Research and Projects Ruth Ladenstein 92 Services, Administration, PR and Donations Department Respective Departments Appendix 95 Scientific Advisory Board 96 Awards 97 Completed MSc Diplomas and PhD Theses 98 External Grants and Research Funding Bodies 102 Publications 110 Imprint 111 Acknowledgements 3 25 Jahre St. Anna Kinderkrebsforschung Ein kurzer Rückblick 17 Vorwort Forschungsbericht Leukämien 20 Immunologische Diagnostik Michael N. Dworzak 24 Biologie der Leukämien Renate Panzer-Grümayer 30 Leukämiegenetik Sabine Strehl Solide Tumoren 36 Tumorbiologie Peter F. Ambros 42 Molekularbiologie Solider Tumoren Heinrich Kovar Immunologie 48 Tumor-Immunologie Thomas Felzmann 54 Klinische Zellbiologie und FACS Core Unit Gerhard Fritsch 60 Transplantations-Immunologie Andreas Heitger 66 Entwicklung zellulärer Therapeutika Wolfgang Holter 72 Molekulare Microbiologie und Labdia Labordiagnostik GmbH Thomas Lion 80 Klinische Forschung S 2 IRP, Studien und Statistik Ruth Ladenstein 92 Service-Einrichtungen, Administration, PR und Spendenabteilung Entsprechende Abteilungen Anhang 95 Wissenschaftlicher Beirat 96 Preise 97 Abgeschlossene Diplomarbeiten und Dissertationen 98 Extern geförderte Projekte und Fördergeber 102 Publikationen 110 Impressum 111 Danksagung

10 Preface Vorwort It is amazing: In 2013, the Children s Cancer Research Institute celebrates its 25th anniversary. Bottle-fed by donations, supported by many benefactors, and raised on competitive grants and continuing philanthropy, the CCRI has come of age. At the end of 2012, the founding father and head of the CCRI, Prof. Helmut Gadner, retired from the directorship of the institute, and a new director, Prof. Wolfgang Holter, took over. Thus, 2012 marked the end of a remarkably fruitful and exciting era in the development of the CCRI. While we are all very much looking forward to a new era in the history of this institute, we are also looking back with gratitude on those years in which Prof. Gadner nursed the CCRI from a mere idea in his head to an internationally renowned research institute that gives children with cancer in Austria access to research results, as well as state-of-the art diagnostics and treatments. In these past years, biomedical research has achieved significant progress and experienced several technological revolutions. The CCRI has always kept up with these important developments, and has contributed significantly to the translation of these achievements into paediatric cancer research. This also holds true for the period 2011/12, documented in this bi-annual report. The adaptation of modern genomic and biological concepts of cancerogenesis, immune surveillance, and targeted therapy to the specifics of childhood cancer is achieved by a highly motivated multidisciplinary team of CCRI researchers from different countries, of which ambitious graduate and PhD students form an indispensable part. Guided by our experienced group leaders and postdocs, several of these students successfully completed their theses in the reporting period. The strength of CCRI research is based on its close proximity to the clinics at St. Anna Kinderspital. To further strengthen the practical and intellectual relationship between these two institutions, we have installed an in-house program especially supporting clinical-translational research driven by treating physicians from the hospital. In addition, the area of clinical research has further expanded, and the CCRI has taken leadership of a European network (ENCCA) to improve multi-centric clinical and translational research through collaboration, coordination, and communication with European health authorities. ENCCA is only one example of several, in which CCRI researchers successfully applied to the European commission for funding of collaborative initiatives on an international level. This success has been greatly facilitated by our dedicated research support office which has been of invaluable help in the successful recruitment of a considerable number of competitive grants supporting high-end research at the CCRI. These grants and the continuous support of our donors and mentors allow the CCRI to continue growing and prospering. A new research group, working on the development of cellular therapeutics, was established with the arrival of the new director of the institute. The increasing needs for bioinformatics analyses of high throughput genomics data and for innovative in vivo models is met by the recruitment of an additional data analyst and a new junior research group, respectively, in In order to fulfill our responsibility towards our donors, we keep them informed on research outcomes and their application to the benefit of sick children and for this reason have also invested in a science communication team. This report is the most recent product of their important work. Heinrich Kovar Scientific Director Es ist erstaunlich: 2013 feiert das Children s Cancer Research Institute (CCRI) bereits seinen 25. Geburtstag. Von Spenden und vielen kompetitiven Projektförderungen genährt, unterstützt von anhaltendem Wohlwollen wuchs das Institut heran. Ende 2012 ist nun der Gründungsvater und langjährige Leiter des CCRI, Prof. Helmut Gadner, in den wohlverdienten Ruhestand getreten, und ein neuer Direktor, Prof. Wolfgang Holter, hat das Institut übernommen. So markiert 2012 das Ende einer bemerkenswerten, fruchtbaren und aufregenden Periode in der Entwicklung des CCRI. Während wir uns schon sehr neugierig auf eine neue Ära in der Geschichte des Institutes freuen, blicken wir auch voll Dankbarkeit auf die Jahre zurück, in denen Prof. Gadner das CCRI von einer Idee in seinem Kopf zu einer international höchst anerkannten Forschungseinrichtung geführt hat, die krebskranken Kindern in Österreich Zugang zu den neuesten wissenschaftlichen Ergebnissen in Diagnostik und Therapie ermöglicht. In diesen vergangenen Jahren machte die biomedizinische Forschung signifikante Fortschritte und erlebte mehrere technologische Revolutionen. Das CCRI hat immer mit diesen Entwicklungen Schritt gehalten und trug maßgeblich zur Umsetzung dieser Errungenschaften für die Erforschung von und den Einsatz bei Krebserkrankungen des Kindesalters bei. Das gilt auch für die Periode 2011/12, die in diesem Jahresbericht dokumentiert wird. Die Anpassung moderner genomischer und biologischer Konzepte der Krebsentstehung, Immunüberwachung und gezielter Therapien an die speziellen Eigenheiten von Kinderkrebserkrankungen wird von einem hoch motivierten, multidisziplinären Team von CCRI Wissenschaftlern getragen, in dem ambitionierte Diplom-/Master und DissertationsstudentInnen eine wesentliche Rolle spielen. Angeleitet von erfahrenen GruppenleiterInnen und PostdoktorandInnen konnten mehrere StudentInnen ihre Dissertation im Berichtszeitraum abschließen. Die Stärke der Forschung am CCRI liegt in der großen Nähe zum St. Anna Kinderspital. Um die enge Zusammen arbeit von Klinikern und Forschern weiter zu stärken, haben wir ein Programm zur Förderung von klinisch-translationalen Projekten eingerichtet, welche durch behandelnde Ärzte des Kinderspitals vorangetrieben werden. Zudem wurde die klinische Forschung weiter ausgedehnt, und das CCRI übernahm die Führung eines europäischen Netzwerkes (ENCCA), dessen Ziel die Verbesserung multi-zentrischer klinischer und translationaler Studien durch Zusammenarbeit, Koordination und Kommunikation mit europäischen Gesundheitsbehörden ist. ENCCA ist nur ein Beispiel von mehreren, in denen CCRI Wissenschaftler erfolgreich Unterstützung für kollaborative Initiativen auf internationaler Ebene von der Europäischen Kommission einwerben konnten. Dieser Erfolg wurde durch die Einrichtung eines Research Support Office erleichtert, welches von unschätzbarer Hilfe in der Akquisition einer beeindruckenden Anzahl kompetitiver Drittmittelprojekte war. Diese Projekte und die fortgesetzte Unterstützung unserer SpenderInnen und MentorInnen ermöglichten ein weiteres Wachstum des CCRI. Mit der Ankunft des neuen Institutsdirektors wurde eine neue Arbeitsgruppe, die sich mit der Entwicklung zellulärer Therapeutika beschäftigt, etabliert. Der steigende Bedarf an bioinformatischen Analysen von Hochdurchsatz genomischen Daten sowie von innovativen in vivo Modellen erfordert 2013 sogar die Einstellung eines weiteren Datenanalysten und Anwerbung einer jungen neuen Arbeitsgruppe. Um der Verantwortung gegenüber unseren SpenderInnen gerecht zu werden, informieren wir sie über den Einsatz unserer Mittel für Forschung und deren Anwendung zum Wohl kranker Kinder und haben dafür auch in ein Wissenschaftskommunikationsteam investiert. Der vorliegende Jahresbericht ist das bislang letzte Produkt seiner wichtigen Arbeit. St. Anna Kinderkrebsforschung/CCRI Scientific Report Heinrich Kovar Wissenschaftlicher Leiter

11 Research Report Forschungs bericht

12 Leukaemias Immunological Diagnostics Leukämien Immunologische Diagnostik Group leader Michael N. Dworzak Staff scientist Zvenyslava Husak Diploma/MSc student Romana Breitler 1 Technician Angela Schumich Susanne Suhendra 2 1 since Dec since Aug. 2011

13 Research focus Innovative diagnostic tools for paediatric leukaemia Our group s research focus resides in developing and validating new diagnostic methods based on flow cytometry mainly in the field of childhood leukaemia and lymphoma, which make up about 50% of all cancer cases in children and adolescents. Our working directions embrace investigations into disease-associated peculiarities of protein ex pression which can be exploited clinically for elaborate diagnostics [1], risk stratification and treatment tailoring to individual needs [2]: e.g. highly sensitive and specific detection of minimal residual disease in acute lymphoblastic as well as myeloid leukaemia1. In an additional but related focus we also aim at supporting novel therapeutic options against childhood leukaemias with new diagnostic approaches, e.g. by deciphering the activated signalling network of leukaemic cells potentially relevant for patient-tailored signal transduction inhibitor treatment2, or by unravelling signal regulation towards augmenting anti-leukaemic defence by the innate immune system [3]. 1 ENCCA grant ( ) 2 WWTF grant Nr. LS ( ) Forschungsschwerpunkt Innovative immunologische Diagnostik für Leukämie im Kindesalter Die Entwicklung und Validierung neuer diagnostischer Methoden basierend auf Durchflußzytometrie ist das Hauptziel unserer Forschungsgruppe. Dabei konzentrieren wir uns vor allem auf die pädiatrischen Leukämien sowie Lymphome, die gemeinsam etwa 50% aller Krebserkrankungen im Kindes- und Jugendalter ausmachen. Zusammenfassend sind die Themen unserer Arbeit einerseits die krankheitsassoziierten Besonderheiten in der Proteinexpression und die sich daraus ergebenden Möglichkeiten für Feindiagnostik [1], Prognoseevaluation, Risikostratifizierung und individualisierte Behandlungsplanung [2], basierend vor allem auf hochsensitiver und spezifischer Detektion mini maler Resterkrankung sowohl bei akuter lymphoblastischer wie auch bei myeloischer Leukämie1. Andererseits beschäftigen wir uns auch mit leukämiebiologischen Fragestellungen2. Wir analysieren die Zellsignalwegaktivierung in Hinblick auf den patientengerechten Einsatz neuer Medikamente (Signalweginhibitoren) bzw. auf neue Möglichkeiten, die antileukämische Immunabwehr zu stimulieren [3]. 1 ENCCA grant ( ) 2 WWTF grant Nr. LS ( ) Specific project CD99 and HSP70 crosstalk in ALL cells increases NK cytotoxicity CD99, an antigen implicated in cell survival and adhesion, is strongly expressed on Ewing tumours and on acute leukaemias. We previously found that modulation of this antigen induces cell death in TEL/AML1-positive ALL [1]. We also observed that CD99-modulation up-regulates the heat shock protein hsp70 in leukaemic cells. Based on these findings, we speculated that CD99-mediated hsp70 up-regulation would induce NK-cell cytotoxicity. In our subsequent investigations supported by the Austrian National Bank1 we demonstrated that CD99-mediated hsp70 up-regulation induces increased NK-cell cytotoxicity against ALL cells, both in primary samples and cell lines, but only weakly if at all against Ewing tumour cell lines [2]. This observation puts CD99-targeting forward as a potential tool to augment defence mechanisms of the immune system against ALL. 1 ÖNB grant 13081; For further reading [1] Husak, Printz et al [2] Husak and Dworzak 2012 Cell counts s HSP70* Fig. 1 HSP up-regulation in primary ALL cells (red: CD99stimulation; blue and grey: (mock) controls. % of apoptotic targeted cells BCP-ALL control DN16 0:1 2.5:1 10:1 E:T ratio s HSP70** % of apoptotic targeted cells cy HSP70** Jurkat P< control DN16 0 0:1 1:1 2.5:1 10:1 E:T ratio Fig. 2 Apoptosis induction by CD99 stimulation (grey line) versus control (black) with and without NK-cells in soaring ratios versus target ALL cells [2]. St. Anna Kinderkrebsforschung/CCRI Scientific Report Leukaemias In collaboration with Prof. Giusepe Basso, Laboratory of Pediatric Onco-Hematology, University of Padova, Italy. Prof. Andrea Biondi and Dr. Giuseppe Gaipa, Tettamanti Research Center, Monza University Milano-Bicocca, Italy. Dr. Richard Ratei and Dr. Leonid Karawajew, Zellmarkerlabor, RRK, HELIOS Klinikum Berlin, Charite MS, Berlin, Germany. Prof. Dirk Reinhardt, Abteilung für Kinderheilkunde Onko-Haematologie, Medizinische Hochschule Hannover, Hannover, Deutschland. Prof. Veronika Sexl, Vet. Med. Uni. Wien, Wien, Österreich In Zusammenarbeit mit Prof. Giusepe Basso, Laboratory of Pediatric Onco-Hematology, University of Padova, Italy. Prof. Andrea Biondi and Dr. Giuseppe Gaipa, Tettamanti Research Center, Monza University Milano-Bicocca, Italy. Dr. Richard Ratei and Dr. Leonid Karawajew, Zellmarkerlabor, RRK, HELIOS Klinikum Berlin, Charite MS, Berlin, Germany. Prof. Dirk Reinhardt, Abteilung für Kinderheilkunde Onko-Haematologie, Medizinische Hochschule Hannover, Hannover, Deutschland. Prof. Veronika Sexl, Vet. Med. Uni. Wien, Wien, Österreich For further reading [1] Fišer, Sieger et al [2] Gaipa, Cazzaniga et al [3] Husak and Dworzak 2012 Literaturangaben [1] Fišer, Sieger et al [2] Gaipa, Cazzaniga et al [3] Husak and Dworzak 2012

14 Leukaemias Biology of Leukaemias Leukämien Biologie der Leukämien 1 since Aug since May since Febr maternity leave from Nov since Aug since May Vice Director Group leader Renate Panzer-Grümayer Postdoctoral fellows Reinhard Grausenburger Kamilla Malinowska-Ozdowy 1 Maria Morak PhD students Stephan Daniel Bastelberger 2 Gerhard Fuka Ulrike Kaindl Christine Nassimbeni 3 Technicians Susanna Fischer Andrea Inthal 4 Astrid Mecklenbräuker 5 Marion Zeginigg 6 Clinicians, St. Anna Children s Hospital Andische Attarbaschi Georg Mann LabDia Labordiagnostik GmbH Oskar A. Haas 7

15 Research focus Unraveling leukaemia pathogenesis to improve prognosis of affected children Childhood acute lymphoblastic leukaemia (ALL), the most frequent cancer in childhood and adolescence, has reached an overall cure rate of approximately 80% when treated according to contemporary risk-directed protocols. Yet despite this remarkable progress, a substantial proportion of cases still suffers a relapse, making leukaemia the 4th most common cause of death in this age group. Consequently, current research focuses on poorly responding ALL subgroups and the identification of new genetic markers. Additionally, given the high cure rates of children with ALL, novel treatment strategies that are less toxic than the currently applied regimens are urgently needed. Therefore, the ultimate goal of our research is to identify and characterise new prognostic and predictive molecular lesions but also to understand how such changes collude to produce and sustain overt leukaemia, progress to relapse and cause drug resistance. To reach this ambitious goal, we i) try to understand why and how leukaemia develops and progresses, and ii) use molecular methods to assess the in vivo treatment response of children with ALL. What mutations drive leukaemia? The main focus of our basic and translational research lies on two large, genomically homogenous ALL subgroups, comprising approximately 20% of all ALL cases each. The first subgroup carries the ETV6/RUNX1, the second a high hyperdiploid karyotype (HD). They share similar clinical features, as both generally lack high risk criteria and respond rapidly to initial chemotherapy. They relapse, however, in up to 20% of cases from which a substantial proportion is resistant to treatment [1]. Both genetic entities have been shown to develop during fetal life, and need in addition to the ETV6/RUNX1 gene fusion and the non-disjunction event that leads to the gain of additional chromosomes cooperating aberrations for progression to overt leukaemia [3][4]. During the last two years, we specifically addressed the function of ETV6/RUNX1 in the fully malignant cell, as well as the timing and nature of presumably pivotal secondary aberrations in both ALL subgroups [1][2][5][6]. Why do some leukaemias re-occur? To gain new insights into the relapse mechanisms, we have employed high resolution SNP arrays and, more recently, also next generation sequencing, for the unbiased genome-wide identification of copy number aberrations and somatic sequence mutations in various leukaemia subgroups. These studies are complemented by targeted re-sequencing and functional analysis of candidate genes. Thereby we detected CREBBP deletion and sequence mutations in more than half of all HD ALL cases at relapse. Moreover, these mutations seem to prevail at initial presentation of relapse cases albeit to a lesser extent than at relapse. Thus, CREBBP mutations might eventually be explored as biomarkers for refined risk stratification and customized treatment [2]. Similar strategies were applied to explore relapse mechanisms of ETV6/RUNX1-positive leukaemias and late relapsing T cell precursor ALL. The majority of relapses were either derived from a common ancestral clone or differed completely from the initial leukaemia [1][7]. All these studies required large patient cohorts and sample collections and were only possible through international collaborations. Individualisation of leukaemia treatment Molecular detection of in vivo response to chemo - therapy is currently one of the best predictive parameters and therefore an integral part of most treatment protocols [8][9]. Methods and applications are subjected to continuous improvement and adaptation within the EURO-MRD Group. For further reading [1] Kuster, Grausenburger et al [2] Inthal, Zeitlhofer et al [3] Panzer-Grümayer, Fasching et al [4] Ford, Bennett et al [5] Fuka, Kauer et al [6] Fuka, Kantner et al [7] Szczepanski, van der Velden et al [8] Schrappe, Valsecchi et al [9] Conter, Bartram et al Forschungsschwerpunkt Entschlüsselung der Leukämieentstehung Prognose verbessern Die akute lymphoblastische Leukämie (ALL) ist als häufigste Krebsart des Kindes- und Jugendalters mit derzeitigen risiko-angepassten Therapieprotokollen in ungefähr 80% heilbar. Dieser Erfolg hat dazu geführt, dass nun auch die Lebensqualität bei Kindern mit ALL ein wichtiges Kriterium für die Beurteilung der Therapie darstellt und daher weniger toxische therapeutische Maßnahmen, als die bisher angewandten, notwendig geworden sind. Aus diesem Grund haben wir uns zum übergeordneten Forschungsziel gesetzt, einerseits neue prognostisch relevante molekulare Läsionen zu entdecken und zu charakterisieren, andererseits aber auch generell zum besseren Verständnis beizutragen, wie Mutationen zusammenwirken und zu einer klinisch manifesten Leukämie führen. Darüber hinaus möchten wir untersuchen, ob bestimmte genomische Veränderungen für den Bestand der Leukämieerkrankung notwendig sind, welche Rolle sie in der Rezidiventwicklung spielen und wie sie zu einer Resistenz gegen Chemotherapeutika beitragen. Welche Mutationen sind für ALL wichtig? Der Hauptfokus unserer Grundlagen- und translationalen Forschung liegt auf zwei großen, genomisch einheitlich definierten Untergruppen der ALL, die jeweils ca. 20% aller Leukämien ausmachen. Die eine Gruppe ist durch das Vorhandensein des ETV6/RUNX1 Fusionsgens, die zweite durch einen hyperdiploiden Chromosomensatz charakterisiert; beide Leukämieformen sind generell nicht mit Hochrisiko-Kriterien assoziiert und sprechen sehr gut auf die Ersttherapie an. Nichtsdestoweniger treten bei bis zu 20% der Kinder Rezidive auf. Im Gegensatz zur früheren Annahme, dass diese Rezidive abermals gut auf die Therapie ansprechen, ist bei einer beträchtlichen Anzahl der Patienten nun eine Resistenz gegen die verabreichte Therapie beobachtet worden [1][2]. Beide Leukämieformen entstehen bereits während der fötalen Entwicklung im Mutterleib und benötigen weitere Mutationen, um eine klinisch manifeste Leukämie zu erzeugen [3][4]. Während der letzten zwei Jahre haben wir uns insbesondere auf die Funktion von ETV6/RUNX1 in der leukämischen Zelle, sowie die zeitliche Abfolge und Be - schaffenheit von kritischen sekundären Veränderungen in beiden Leukämiegruppen konzentriert [1][2][5][6]. Warum treten Leukämien erneut auf? Um neue Erkenntnisse auf dem Gebiet der Rezidiventwicklung zu gewinnen, haben wir hochauflösende SNP Arrays und genomweite Sequenzierungen für den uneingeschränkten Nachweis von genetischen Veränderungen verwendet. Diese Studien wurden durch funktionelle Analysen ausgewählter Gene ergänzt. Wir konnten so einerseits bei hyperdiploiden Leukämien und ETV6/RUNX1-positiven, andererseits bei T Zell- Leukämien feststellen, dass die meisten Rezidive von einer gemeinsamen Vorläuferzelle abstammen oder sogar komplett unterschiedlich sind [1][2][7]. Da alle diese Studien große Patientenzahlen benötigen, wurden sie im Rahmen von internationalen Kollaborationen, insbesondere der BFM Studiengruppen, durchgeführt. Erfassung des Therapieansprechens Mittels hochauflösender molekularer Methoden bestimmen wir das individuelle Therapieansprechen aller Kinder mit ALL in Österreich. Diese Form der Diagnostik stellt derzeit einen der besten prädiktiven Parameter da und ist in die meisten Therapiestudien integriert [8][9]. Die Methoden und Anwendungen werden innerhalb der Europäischen MRD Gruppe ständig verbessert und erweitert. Literaturangaben [1] Kuster, Grausenburger et al [2] Inthal, Zeitlhofer et al [3] Panzer-Grümayer, Fasching et al [4] Ford, Bennett et al [5] Fuka, Kauer et al [6] Fuka, Kantner et al [7] Szczepanski, van der Velden et al [8] Schrappe, Valsecchi et al [9] Conter, Bartram et al St. Anna Kinderkrebsforschung/CCRI Scientific Report Leukaemias

16 Specific project ETV6/RUNX1 perturbs key processes and is essential for leukaemia To evaluate the impact of ETV6/RUNX1 on the regulation of genes and pathways in leukaemia, we performed shrna-mediated knock-down of the endogeneous fusion gene in two leukaemic cell lines and investiga ted the ensuing consequences on genome-wide gene expression patterns and deducible regulatory functions [1]. We thereby identified 777 genes whose expression was substantially altered with approximately equal numbers up- or down-regulated. The upregula ted set was significantly enriched with genes included in cell activation, immune response, apoptosis, signal transduction and development, and differentiation categories (Fig. 1). In the ETV6/RUNX1 knock-down set, only PI3K/AKT/mTOR signaling and haematopoietic stem cell category were observed. Comparable gene expression signatures obtained from primary ETV6/RUNX1-positive ALL samples also underlined the relevance of these pathways and molecular functions. As a consequence, we analysed the interaction between the fusion gene and PI3K/AKT/mTOR pathway activation in more detail and showed that ETV6/RUNX1 indeed activates this pathway and that pharmacological inhibition significantly increases the apoptosis rate in these leukaemias. We also found that PI3K/mTOR inhibitors sensitised resistant cell lines to drugs. Our findings thus demonstrate that together with a severely impaired repopulation capacity of leukaemia cell lines upon suppression of ETV6/RUNX1 in NOD/SCID mice continuous expression of the ETV6/RUNX1 fusion gene i) interferes with key regulatory functions that shape the biology of this leukaemia subtype and ii) is essential for disease maintenance. Importantly, these results provide the first rationale and justification for targeting the fusion gene and the PI3K/AKT/mTOR pathway therapeutically [2]. This is of particular relevance given the enormous clonal heterogeneity of secondary aberrations that precludes their therapeutic targeting and leaves ETV6/RUNX1 as the only common marker [1][2][3]. A B Fig. 1 Meta-groups of functional annotations for up-regulated genes upon E/R knock-down. Meta-groups were curated based on gene clustering of annotation terms. A: Top 100 annotation terms from knock-down-up genes, their P-values and their affiliation to meta-groups. Similarity of the metagroups was based on the number of shared genes. For distance calculations between the meta-groups genes from all contributing terms were taken together. B: Change in expression of individual genes in meta-groups that contain significant annotation terms. The color code at the bottom of the figure indicates the extent of log2-fold changes in gene expression. Specific project Challenging P2RY8-CRLF2 s role as main relapse-driving force in leukaemia The P2RY8-CRLF2 fusion defines a particular relapseprone subset of ALL in non-down Syndrome (DS) children. It derives from an interstitial deletion in the PAR1 region, results in the overexpression of the cytokine receptor-like factor 2 (CRLF2) and practically never concurs with ETV6-RUNX1, MLL, TCF3 or BCR-ABL fusions. Previous reports suggested that P2RY8-CRLF2 represents a driver mutation and that the abrogation of its signaling may by therapeutically exploited. Prompted by the observation of subclonal distribution of the fusion, we investigate whether and to what extent different clone sizes influence disease and relapse development. For this purpose, we quantified the genomic P2RY8-CRLF2 fusion product and correlated it with the corresponding CRLF2 expression levels in patients enrolled in the BFM-ALL 2000 protocol in Austria. Of 268 cases without recurrent chromosomal translocations and high-hyperdiploidy (representing approximately 50% of all cases), 67 (25%) were P2RY8-CRLF2-positive [4]. The respective clone sizes were 20% in 27% and <20% in 73% of the cases. The cumulative incidence of relapse of the entire fusionpositive group was clone size independent and significantly higher than that of the fusion-negative group (35±8% vs. 13±3%, P=0.008); also, these cases were primarily confined to the non-high-risk groups. Of 22 P2RY8-CRLF2-positive diagnosis/relapse pairs, only 4/8 had the fusion-positive dominant clone conserved at relapse, whereas none of the original 14 fusion-positive small clones reappeared as the dominant relapse clone. We conclude that the majority of P2RY8-CRLF2- positive clones are small at diagnosis and virtually never generate a dominant relapse clone. Our findings therefore suggest that P2RY8-CRLF2-positive clones do not have the necessary proliferative or selective advantage to evolve into a disease-relevant relapse clone [4][5]. In collaboration with Kofler R. and Rainer J., Tyrolian Cancer Research Institute and Biocenter Division Molecular Pathophysiology, Innsbruck Medical University, Austria Bauer E., Kanter H.P. and Stoiber D., Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria Hall A. and Russel L., Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne UK Metzler M., Department of Paediatrics, University of Erlangen-Nuernberg, Erlangen, Germany Meyer L.H., Universitätsklinik für Kinder- und Jugendmedizin, Ulm, Germany Meyer C. and Marschalek R., Institute of Pharmacological Biology/DCAL, Goethe-University, Frankfurt, Germany Harbott J., Oncogenetic laboratory, Dept. Ped. Haematol/Oncol., Justus-Liebig University, Gießen, Germany Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)-Berlin-Frankfurt-Münster (BFM) Study Group, European Study Group for the Detection of Minimal Residual Disease (Euro-MRD-Group). For further reading [1] Fuka, Kauer et al [2] Fuka, Kantner et al [3] Kuster, Grausenburger et al [4] Attarbaschi, Morak et al [5] Morak, Attarbaschi et al St. Anna Kinderkrebsforschung/CCRI Scientific Report Leukaemias

17 Leukaemias Genetics of Leukaemia Leukämien Leukämiegenetik Group leader Sabine Strehl Postdocs Dagma Denk 1 Klaus Fortschegger Karin Nebral 2 PhD students Stefanie Anderl 3 Sara Colomer Lahiguera 4 Dagmar Denk 5 Diploma/MSc student Teresa Preglej 6 Technician Margit König Clinicians, St. Anna Children s Hospital Andishe Attarbaschi Michael N. Dworzak Georg Mann 1 since Aug until Febr since Apr since Dec until July since Sept. 2012

18 Research focus Genetic and biological characterisation of paediatric acute leukaemia Although in the majority of leukaemia the primary genetic alterations responsible for the pathogenesis of the disease have already been unraveled [1][2], in many instances the underlying molecular genetic lesions are still unknown. Furthermore, the biological consequences as well the clinical impact of numerous specific genetic alterations remain to be determined. Therefore, the research of the Genetics of Leukaemia group is centred around two main aspects: On the one hand, we focus on the identification of novel genetic alterations that are involved in the pathogenesis and progression of childhood acute leukaemia and the evaluation of genetic lesions as potential predictive biomarkers for the refinement of risk stratification and risk-adapted therapy. On the other hand, our aim is to gain further insights into the functional consequences of specific genetic alterations, in particular those potentially oncogenic fusion genes that have been identified by our group [3][4]. Genetic alterations and prognosis To accomplish these tasks, we conduct comprehensive population-based screening studies for genetic alterations in leukaemia samples of patients enrolled in the Austrian BFM clinical trials employing a range of molecular genetic approaches. Genetic and clinical datasets are then used to determine whether some recurring genetic alteration may serve as biomarkers for treatment failure and whether its occurrence may, therefore, justify therapy intensification. The assessment of the prognostic relevance of specific genetic aberrations is performed in close collaboration with the clinicians of the St. Anna Children s Hospital and within the framework of the International BFM Study Group. PAX5 aberrations in B-cell leukaemia To gain further insights into the pathogenesis of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), we are focusing on the functional consequences of PAX5 alterations. The rationale for the selection of this particular gene is derived from the fact that PAX5 plays a pivotal role in B-cell commitment and maintenance and is affected by mutations including deletions, amplifications, point mutations, and gene rearrangements in about 30% of paediatric BCP-ALL, suggesting a crucial role in the pathogenesis of the disease. Based on our identification of several PAX5 fusion genes, which encode potentially oncogenic aberrant transcription factors [3 5], we now aim to elucidate their role in leukaemogenesis. References [1] Pui, Carroll et al [2] Pui, Mullighan et al [3] Nebral, König et al [4] Nebral, Denk et al [5] Denk, Nebral et al Forschungsschwerpunkt Genetische und biologische Charakterisierung akuter Leukämien In der Mehrheit der akuten Leukämien im Kindes- und Jugendalter wurden die für die Krankheitsentstehung verantwortlichen primären genetischen Veränderungen bereits aufgeklärt [1][2]. Dennoch sind in vielen Fällen die genetischen Aberrationen, die zur Leukämieentwicklung führen, nach wie vor unerforscht, und sowohl deren biologische Auswirkungen als auch deren Einfluss auf die Prognose der PatientInnen unbekannt. Deshalb fokussiert die Arbeitsgruppe für Leukämiegenetik ihre Arbeit auf zwei Schwerpunktthemen: Einerseits auf die Identifizierung genetischer Veränderungen, die in die Krankheitsentstehung und das Fortschreiten einer akuten Leukämie involviert sind, sowie die Bewertung der prognostischen Relevanz bestimmter genetischer Veränderungen, die in Folge als sogenannte Biomarker zur Risikobewertung und Therapieabstimmung herangezogen werden könnten. Andererseits ist es Ziel unserer Forschungsarbeit, die biologischen Auswirkungen bestimmter genetischer Veränderungen zu erforschen, insbesondere jener Fusionsgene, die unsere Arbeitsgruppe identifiziert hat [3][4]. Die Bedeutung genetischer Veränderungen Um diese Ziele zu erreichen, führen wir umfassende genetische Analysen der leukämischen Zellen aller PatientInnen durch, die in den österreichischen Leukämiestudien registriert sind. Dafür setzen wir eine Reihe molekularer Techniken ein. Um festzustellen, ob eine spezifische genetische Veränderung mit einem hohen Risiko eines Therapieversagens einhergeht und als prognostisch aufschlussreicher genetischer Biomarker eingesetzt werden kann, werden genetische und klinische Daten miteinander korreliert. Die Bewertung der prognostischen Relevanz der genetischen Marker, die zu einer verfeinerten Einteilung in Risikogruppen führen könnte, wird in enger Zusammenarbeit mit den ÄrztInnen des St. Anna Kinderspitals und der Inter nationalen BFM Studiengruppe durchgeführt. Leukämie und PAX5 Um neue Erkenntnisse in Bezug auf die Krankheitsentstehung der B-Vorläuferzell akuten lymphatischen Leukämie (B-ALL) zu gewinnen, erforschen wir schwerpunktmäßig die Auswirkungen von Veränderungen des PAX5 Gens. Die Motivation, gerade dieses Gen zu untersuchen, begründet sich darauf, dass PAX5 eine zentrale Funktion in der Entwicklung normaler B-Zellen und deren Erhaltung spielt und in ungefähr 30% aller BALL von genetischen Veränderungen Deletionen, Amplifikationen, Mutationen und Genrearrangements, die zu Genfusionen führen betroffen ist. Naheliegender weise könnte PAX5 deshalb auch eine Rolle in der Leukämieentstehung spielen. Ausgehend von unserer Identifikation einiger PAX5 Partnergene [3 5] erforschen wir nun, welche Rolle diese potentiell onkogenen Fusionsgene in der Pathogenese der akuten Leukämie spielen. Literaturangaben [1] Pui, Carroll et al [2] Pui, Mullighan et al [3] Nebral, König et al [4] Nebral, Denk et al [5] Denk, Nebral et al St. Anna Kinderkrebsforschung/CCRI Scientific Report Leukaemias

19 Specific project Functional consequences of PAX5 fusion proteins In about 30% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), PAX5, a master regulator of B-cell development, is affected by genetic alterations including deletions, amplifications, point mutations, and the formation of fusion genes [1]. While deletions and point mutations frequently coincide with known sentinel alterations such as the ETV6-RUNX1 and BCR-ABL1 fusion genes, and are therefore considered as secondary events, PAX5 rearrangements, which result in the expression of potentially oncogenic fusion genes, most likely represent primary genetic events. The chimeric proteins encoded by the fusion transcripts are hypothesised to act as trans-dominant aberrant transcription factors, which antagonize wild-type PAX5 function. Based on our own studies and those of others, in which it has been determined that the N-terminus of PAX5 is fused to a markedly heterogeneous group of C-terminal fusion partners including transcription factors, structural proteins or the tyrosine kinase JAK2 [1 5], we currently aim to investigate the biochemical and functional properties of these distinct chimeric proteins. Properties of PAX5 fusion proteins The consistent retention of the N-terminal PAX5 DNAbinding paired domain, which is fused to the C-terminal domains of one of the highly diverse partner proteins, indicates that PAX5 chimeric proteins may have properties both common to and distinct from those of wild-type PAX5. Indeed, independent of the genuine subcellular localisation of the individual partner protein, all PAX5 fusion proteins display a predominantly nuclear localisation (Fig. 1), which appears to be mainly dictated by the paired domain. Intriguingly, in contrast to the cytoplasmic localisation of all other JAK2 fusion proteins analysed to date, PAX5-JAK2 is also a nuclear protein. As a second common key characteristic of all PAX5 fusion proteins, the PAX5 paired domain mediates their DNA interactions at specific PAX5 target sequences, albeit with obviously variable affinities, pointing at potential differences in their effects on gene transcription. In contrast to these common biochemical properties, our experiments showed that only some PAX5 fusion proteins are capable of homooligomerisation while others are not. Since PAX5 wildtype protein is known to bind to DNA as monomer, the interfaces for self-interaction are provided by distinct moieties such as coiled-coil domains present in the respective partner proteins. In terms of their impact on PAX5 target gene expression, at least in reporter gene assays, some of the PAX5 fusion proteins appeared to have activation potential rather than mere antagonizing or repressive capacity. However, in a murine cell line model, the effect of PAX5 chimeric proteins on the transcriptional activation of the PAX5 target Cd79a could not be confirmed and thus, additional studies are required to determine the impact of PAX5 chimeric proteins on PAX5 target gene transcription. Constitutive kinase activity of PAX5-JAK2 Intriguingly, amongst all PAX5 fusion proteins, PAX5- JAK2 appears to have a unique function, because it has constitutive kinase activity and activates the JAK-STAT signaling pathway. More specifically, PAX5JAK2 itself is phosphorylated and, in turn, phosphorylates and activates downstream STATs. Furthermore, gene expression profiling of PAX5-JAK2 positive patient samples revealed high similarities with BCR-ABL1 and JAK2-mutated BCP-ALL, further substantiating that in the primary leukaemia, the JAK-STAT pathway is indeed activated. Importantly, at least in vitro, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors, rendering it a potential target for therapeutic intervention. References [1] Mullighan, Goorha et al [2] Nebral, König et al [3] Nebral, Denk et al [4] Coyaud, Struski et al [5] Denk, Nebral et al Specific project Treatment outcome of childhood leukaemia with specific genetic alterations In international collaborations, we continually con tribute to studies regarding the prognostic relevance of specific genetic alterations in the context of the I-BFM and in comparison to other treatment protocols. These multicentre studies are a necessity to increase the size of patient cohorts to gain more statistical power, and to analyse rare disease entities. MLL and CRLF2 rearrangements The I-BFM study group has extended its meta-analysis assessing the clinical impact of specific MLL rearrangements in paediatric acute myeloid leukaemia (AML) and showed that not only the MLL translocation partner itself [1] but also secondary cytogenetic aberrations independently predict clinical outcome [2]. Moreover, in a comparative study it has been determined that the cumulative relapse incidence of P2RY8-CRLF2+ patients treated on the AIEOP-BFM or UK trials did not differ statistically. However, the relapse rate of patients was much higher in patients enrolled in UK trials suggesting treatment-related differences [3]. translocations In another international project with the aim to ascertain the true incidence of translocations in BCP-ALL and to further characterise this subtype of leukaemia, we have analysed 350 cases lacking the major sentinel fusion genes by an break-apart FISH assay and have identified translocations in ~5% of patients. This study confirmed CRLF2 to be the most frequent partner gene, however, in 50% of cases the translocation partners remain unknown and their identification is still ongoing. STAT5B-RARA-positive acute promyelocytic leukaemia Furthermore, we have determined that, in contrast to PML-RARA+ acute promyelocytic leukaemia (APL), which is responsive to treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), the STAT5B-RARA fusion variant defines a highly relapse-prone APL subgroup, which is insensitive to both therapeutic agents. Hence, the accurate identification of this rare subtype of APL is therefore essential for therapeutic decision-making [4]. In collaboration with The Austrian (represented by Andishe Attarbaschi, Michael N. Dworzak, Georg Mann, all St. Anna Children s Hospital) and the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG). References [1] Balgobind, Raimondi et al [2] Coenen, Raimondi et al [3] Attarbaschi, Morak et al [4] Strehl, König, et al Fig. 1 The indicated PAX5 fusion proteins predominantly localise to the nucleus as determined by immunofluorescence and confocal microscopy; white arrow points out punctate cytoplasmic staining and white bars indicate 20μm. St. Anna Kinderkrebsforschung/CCRI Scientific Report Leukaemias

20 Solid Tumours Tumour Biology Solide Tumoren Tumorbiologie Group leader Peter F. Ambros Staff scientist Ingeborg M. Ambros Sabine Taschner-Mandl PhD students M. Reza Abbasi 1 Dominik Bogen 2 Fikret Rifatbegovic 3 Tamara Weiss 4 Diploma/MSc student Magdalena Schwarz 5 Technicians Bettina Brunner-Herglotz Andrea Ziegler Clinicians St. Anna Children s Hospital Leo Kager Ruth Ladenstein 1 since Mar currently at NIH 3 since May since Oct since Sep. 2012

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