Prof. Nicolas Bonadies completed his studies in Human Medicine at the University of Bern in 1998 and was board certified in Internal Medicine in 2005. Subsequently, he dedicated his time to basic research projects covering the topics of blood formation (haematopoiesis) and development of leukaemias (leukemogenesis) from 2006-2009. From the Swiss National Science Foundation (SNSF), he was appointed a postdoctoral fellowship in Cambridge (UK) from 2008-2009. After his return, he completed his residency training with board certifications in Clinical and Laboratory Hematology (FMH, FAMH). His clinical research interests includes health service research and improvement of diagnosis/therapy of myeloid neoplasms with focus on Myelodysplastic Syndromes (MDS) and Myelodysplastic Syndromes/Myeloproliferative Neoplasms (MDS/MPN). He is a member of the SAKK Leukemia Project Group and chair of the Swiss MDS Study Group (SMSG). One of his main projects is the implementation of the Swiss MDS Registry with an associated biobank, which serves in promoting national and international collaborations for precision and personalized medicine. He was appointed a position of senior attending physician in 2017 and an associate professorship in Hematology in 2020. He is the head of the Clinical Research Unit (CHARMS), MDS Centre of Excellence, haematological biobank/registry and deputy head of the in-/outpatient clinic at the Department of Hematology and Central Hematology Laboratory at the Inselspital in Bern.

Prof. Nicolas Bonadies’ research is covering clinical and translational aspects with focus on health service research as well as precision/personalized medicine in patients with MDS and associated disorders. His research interests are broad and cover translational biology of leukemogenesis as well as clinical questions dedicated to improve diagnostics, prediction, prognosis and treatment of patients affected by these heterogeneous, myeloid disorders.

He has implemented a multicentric Swiss MDS Registry/Biobank as well as the HÄM-COHORT. Both are research platforms that are indispensable for advancing precision and personalized medicine, as recent advances in genomics have substantially increased disease heterogeneity and require structural improvements, sharing and pooling of research infrastructures. Using these platforms, many research questions can now be addressed at our institution in collaboration with national and international partners.

Prof. Nicolas Bonadies’ initial research was dedicated to basic research in the field of transcriptional control of normal hematopoiesis as well as myeloid neoplasms (1-8). During his SNSF post-doctoral fellowship at Cambridge University (UK), he focused on the investigation of the transcriptional control of the LMO2 hematopoietic oncogene. For this work, he received the Award in Experimental Hematology of the Swiss Society of Hematology in 2009 (2, 6). Moreover, he investigated the genome-wide transcriptional reprogramming in leukemia mouse models with a combined approach of RNA-expression and ChIP-sequencing using next generation sequencing technologies and bioinformatics approaches, where he discovered that downregulation of a GATA2 transcriptional network plays an important role in the transition to overt leukemia (1).

After his return to Switzerland, he developed a growing interest for shared translational research platforms that allow the investigation of the biology of myeloid neoplasms using primary patient samples. These platforms should provide a commonly shared infrastructure for systematic collection of data and biological samples from patients with rare and genetically heterogeneous disease, such as MDS and related disorders. Such a research platform was not available in Switzerland at that time. Together with hematological colleagues, he founded the SMSG in 2014, where he was the driving force in the development of a shared web-based database (SecuTrial) as well as a biobank for systematic collection of viable cells from bone marrow and peripheral blood - the Swiss MDS Registry/Biobank (SMRB) platform. He is currently the chair of the SMSG and national coordinator of the SMRB platform.

Together with the National Institute for Cancer Epidemiology and Registration (NICER), he has published the population-based epidemiology focusing on trends of incidence, mortality and survival of patients with MDS, AML and Chronic Myelomonocytic Leukemia (CMML) (9-11) (Figure 1). Moreover, he investigated the association of systemic autoimmmune/autoinflammatory manifestations (SIAMs) with MDS and CMML (12) and performed a systematic review with meta-analysis on the efficacy and safety of G-CSF on top of erythropoietin-stimulating agents (ESA) in the treatment of anemia in lower-risk MDS patients (Figure 2) (13). Finally, the SMRB platform offered many opportunities for collaborative project that were dedicated to investigate the utility of microarray-comparative genomic hybridisation (array-CGH) in the diagnosis of MDS patients with normal karyotype (14) and the comparison of histology and cytomorphology in MDS patients (WP4) (15).

With the nationwide implementation of the SMRB platform he initiated the work package 1 (WP1) on this MDS registry/biobank platform, the “I-CARE for MDS” study. This multicentric study is sponsored and coordinated by the SAKK (SAKK 33/18 trial) and Prof. Bonadies is the coordinating investigator in Switzerland. This study consist of three main objectives 1) the development of guideline-based indicators (GBIs) as an international consensus on measurable elements for quality of care for adult patients with MDS, 2) prospective validation of these GBIs with characterization of patient, disease and provider characteristics associated with adherence/non-adherence and 3) investigation of adherence/non-adherence on patient centred outcomes such as quality of life, hospitalisation and survival. His study group has recently published the first objective of the I-CARE study, the international consensus on GBIs for adult MDS patients, which were developed in collaboration with acknowledged international experts in the field (Figure 3) (16).

The translational research projects from his group are focussing on the investigation of the Convergence of Genetic and Epigenetic Alterations in Targetable Oncogenic Pathways in High-risk Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia and the Identification and Validation of Bypassing Oncogenic Pathways in Patients with Relapsed/Refractory Myeloid Neoplasms. In collaboration with PD Dr. Manfred Heller, a bioinformatics PhD student in his lab has developed a phosphoproteome analysis pipeline. This pipeline uses differential phosphoprotein profiles identified by mass-spectrometry that are analysed with a novel bioinformatics tool (Kinase Activity Enrichment Analysis) and which allows inferring kinase activity in myeloid cell lines treated with specific kinase inhibitors. The validation experiments of this KAEA pipeline have been submitted for publication (Figure 4).

There are currently national working packages (WP1-WP6) using the MDS registry/biobank platform as resource for structured data and sample acquisition and sharing. Moreover, the platform allows the exchange of data and samples with international cooperation partners from Austria, Spain and Germany (IC1-IC3). Finally, this platform is used for collection of data and samples for ongoing master and doctoral theses, investigating different aspects of clinical management of patients with MDS and associated disorders.

As previously mentioned, the I-CARE for MDS study (WP1) is sponsored and coordinated by SAKK (SAKK 33/18) and represents a health service research project to investigate the Impact of Guidelines Adherence on Effectiveness and Safety of Health CARE Provided to MDS Patients. The final aim of “I-CARE” is prospective validation and implementation of GBIs that will allow assessing, comparing and improving quality of care within clinical development cycles. The multicentre SAKK 33/18 has started recruitment in 3/2020 and shall run for 4 years, aiming to include 400-600 adult patients with MDS and associated disorders.

The role of the innate immunity in MDS and associated disorders will be investigated in WP2 in collaboration with Prof. R. Allam and Dr. Nicola Andina. WP3 addresses the influence of free plasma iron toxicity and redox-stress on immune subversion and clonal progression in patients with lower risk MDS in collaboration with Prof. V.U. Bacher and PD Dr. M. Fux. In collaboration with PD Dr. Manfred Heller WP5 is investigating The Role of Extracellular Vesicles (EVs) in Myelodysplastic Syndromes. EVs from more than 20 MDS patients have been collected from the MDS registry/biobank platform and analysis of the data with focus on the prototypic composition of mainly danger associated molecular pattern (DAMP) proteins and other mediators of inflammation is ongoing. Characterization of Oncospecific Protein Isoforms as Targets for Myelodysplastic Syndromes will be investigated in the most recent WP6. This project will be done in collaboration with colleagues from the University Hospital Zurich (Prof Dr. Stephan Balabanov, Prof. Markus G. Manz), Nexus at the ETH (Dr. Daniel Stekhoven), Clinical Proteotype Analysis Centre at the ETH (Prof. Bernd Wollscheid) und the Genome Center in Geneva (Dr. Keith Harshman. Prof. Ioannis Xenarios). This project was awarded a PHRT pioneer project grant in 2019, which was dedicated to promote “multi”-omics approaches (DNA-exome seq, RNA seq, proteotypic analysis). In this project oncospecific targets derived from alternatively sliced RNA products will be characterized. These proteins have not been systematically investigated in MDS and might have unique biological and immunogenic properties that could be used for the targeted treatment in MDS patients.

National

WP1: Swiss MDS Study Group  and I-CARE for MDS (SAKK 33/18)

• Dr. med. Nathan Cantoni, KS Aarau
• Dr. med. Gregor T. Stehle, Universitätsspital Basel
• PD Dr. med. Dirk Kienle, Kantonsspital Graubünden
• Dr. med. Tobias Silzle, Kantonsspital St. Gallen
• Dr. med. Geneviéve Favre, Kantonsspital Liestal
• Dr. med. Axel Rüfer, Kantonsspital Luzern
• PD Dr. med. Georg Stüssi, Istituto Oncologico della Svizzera Italiana
• Dr. med. Rudolf Benz, Spital Thurgau
• Dr. med. Adrian Schmidt, Stadtspital Triemli
• Dr. med Cathérine Mengis-Bay, Spital Wallis
• Prof. Dr. med. Dr. rer. nat. Stefan Balabanov, Universitätsspital Zürich
• PD Dr. med. Julia Bohlius
• Prof. sc. nat. David Schwappach, Patientensicherheit Schweiz, Zürich
• Dr. sc. nat. Sämi Schär, SAKK
• Dr. sc. nat. Charlotte Maddox SAKK
• Prof. Dr. med. Jakob Passweg, Basel, Switzerland
• Prof. sc. nat. Jürg Bernhard, UKMO, Inselspital Bern
• Prof. Dr. med. Manuel Haschke, Inselspital Bern
• Others may join later

WP 2: Role of innate immunity in MDS

• Prof. Ramanjaneyulu Allam, UKH-HZL and DMBR, Inselspital Bern
• Dr. med. Dr. phil. Nat. Nicola Andina, UKH-HZL, Inselspital Bern

WP 3: Redox stress in MDS

• Prof. Dr. med. V. Ulrike Bacher, UKH-HZL, Inselspital Bern
• PD Dr. Michaela, Fux, ZLM, Inselspital Bern

WP 5: Extracellular vesicles and proteomics projects in MDS

• PD Dr. Manfred Heller, Head of Proteomics Mass Spectrometry Core Facility, University of Bern
• Dr. Rémy Bruggmann, Head of Interfaculty Bioinformatics Unit, University of Bern

WP 6: Multiomics PHRT project

• Prof. Dr. med. Dr. sc. nat. Stephan Balabanov, Prof. Dr. med. Markus G. Manz, USZ
• Prof. Dr, med. Ulrike Bacher, UKH-HZL, Inselspital Bern
• PD Dr. med. Michael Daskalakis, UKH-HZL, Inselspital Bern
• Dr. Sc. nat. Tata Nageswara Rao, UKH-HZL and DMBR, Inselspital Bern
• Dr. sc. nat. Naomi Porret, UKH-HZL, Inselspital, Bern
• Dr. sc. nat. Gertrud Wiedemann, UKH-HZL, Inselspital Bern
• Dr. Daniel Stekhoven, Dr. Franziska Singer, Nexus ETH, Zurich
• Prof. Dr. sc. nat. Bernd Wollscheid, Dr. Sandra Götze, Clinical Proteotype Analysis Centre ETH, Zurich
• Dr. Keith Harshman. Prof. Prof. Ioannis Xenarios, Genome Center, Geneva

International

International Consensus Group for Development of GBIs

• Prof. David Bowen, Leeds, UK
• Prof. Jaroslav Čermák, Prague, Czech Republic
• Dr. Avinash G. Dinmohamed, Rotterdam, Netherlands
• Prof. Pierre Fenaux, Paris, France
• Prof. Ulrich Germing, Düsseldorf, Germany
• Prof. Eva Hellstrom-Lindberg, Stockholm, Sweden
• Prof. Arjan A. van de Loosdrecht, Amsterdam, Netherlands
• Prof. Michael Pfeilstöcker, Vienna, Austria
• Prof. Uwe Platzbecker, Leipzig, Germany
• Prof. Luca Malcovati, Pavia, Italy
• Prof. Antonio Medina De Almeida, Lisboa, Portugal
• Prof. Moshe Mittelman, Tel Aviv, Israel
• Prof. David P. Steensma, Boston, USA
• Prof. Valeria Santini, Florence, Italy
• Prof. Reinhard Stauder, Insbruck, Austria
• Prof. Argiris Symeonidis, Patras, Greece
• Prof. Theo de Witte, Nijmegen, Netherlands

IP: Proteomics in AML

• International cooperation with Prof. Björn Gjertsen, University of Bergen, Norway

IP1: CMML First Line Treatment 

• International cooperation with PD. Dr. Lisa Pleyer, Salzburg Cancer Research, Austria

IP2: Genetic background of MDS-MPN-U 

• International cooperation with Prof. Francesc Sole, Joseph Carrera Leukaemia Research Institute, Barcelona, Spain 

IP3: Genetic background of hypoplastic MDS

• International cooperation with Prof. Felicitas Thol, Hannover Medical School, Germany

IP4: Guideline adherence in Düsseldorf MDS Registry

• International cooperation with Prof. Ulrich Germing, Heinrich Heine University Düsseldorf Germany

Funding support Nicolas Bonadies (PDF)

1. Bonadies N, Foster SD, Chan WI, Kvinlaug BT, Spensberger D, Dawson MA, et al. Genome-wide analysis of transcriptional reprogramming in mouse models of acute myeloid leukaemia. PloS one. 2011;6(1):e16330.
2. Bonadies N, Gottgens B, Calero-Nieto FJ. The LMO2 -25 Region Harbours GATA2-Dependent Myeloid Enhancer and RUNX-Dependent T-Lymphoid Repressor Activity. PloS one. 2015;10(7):e0131577.
3. Bonadies N, Neururer C, Steege A, Vallabhapurapu S, Pabst T, Mueller BU. PU.1 is regulated by NF-kappaB through a novel binding site in a 17 kb upstream enhancer element. Oncogene. 2010;29(7):1062-72.
4. Bonadies N, Pabst T, Mueller BU. Heterozygous deletion of the PU.1 locus in human AML. Blood. 2010;115(2):331-4.
5. Calero-Nieto FJ, Joshi A, Bonadies N, Kinston S, Chan WI, Gudgin E, et al. HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias. Oncogene. 2013;32(48):5471-80.
6. Landry JR, Bonadies N, Kinston S, Knezevic K, Wilson NK, Oram SH, et al. Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors. Blood. 2009;113(23):5783-92.
7. Vezzoli A, Bonadies N, Allen MD, Freund SM, Santiveri CM, Kvinlaug BT, et al. Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1. Nature structural & molecular biology. 2010;17(5):617-9.
8. Wilson NK, Miranda-Saavedra D, Kinston S, Bonadies N, Foster SD, Calero-Nieto F, et al. The transcriptional program controlled by the stem cell leukemia gene Scl/Tal1 during early embryonic hematopoietic development. Blood. 2009;113(22):5456-65.
9. Benzarti S, Daskalakis M, Feller A, Bacher VU, Schnegg-Kaufmann A, Rufer A, et al. Trends of incidence and survival of patients with chronic myelomonocytic leukemia between 1999 and 2014: A comparison between Swiss and American population-based cancer registries. Cancer epidemiology. 2019;59:51-7.
10. Bonadies N, Feller A, Rovo A, Ruefer A, Blum S, Gerber B, et al. Trends of classification, incidence, mortality, and survival of MDS patients in Switzerland between 2001 and 2012. Cancer epidemiology. 2017;46:85-92.
11. Schnegg-Kaufmann A, Feller A, Baldomero H, Rovo A, Manz MG, Gregor M, et al. Improvement of relative survival in elderly patients with acute myeloid leukaemia emerging from population-based cancer registries in Switzerland between 2001 and 2013. Cancer epidemiology. 2018;52:55-62.
12. Kipfer B, Daikeler T, Kuchen S, Hallal M, Andina N, Allam R, et al. Increased cardiovascular comorbidities in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia presenting with systemic inflammatory and autoimmune manifestations. Seminars in hematology. 2018;55(4):242-7.
13. Affentranger L, Bohlius J, Hallal M, Bonadies N. Efficacy of granulocyte colony stimulating factor in combination with erythropoiesis stimulating agents for treatment of anemia in patients with lower risk myelodysplastic syndromes: A systematic review. Critical reviews in oncology/hematology. 2019;136:37-47.
14. Ouahchi I, Zhang L, Benitez Brito R, Benz R, Muller R, Bonadies N, et al. Microarray-based comparative genomic hybridisation reveals additional recurrent aberrations in adult patients evaluated for myelodysplastic syndrome with normal karyotype. British journal of haematology. 2019;184(2):282-7.
15. Engelbrecht L GK, Schwamborn K, Alpermann T, Bonadies N, Legros M, Flach J, Pabst Th, Banz Y, Bacher U. Correlation of cytomorphology and histopathology in the diagnostic process of myeloid malignancies. Hematology and Medical Oncology 2019. 2019.
16. Stojkov K, Silzle T, Stussi G, Schwappach D, Bernhard J, Bowen D, et al. Guideline-based indicators for adult patients with myelodysplastic syndromes. Blood advances. 2020;4(16):4029-44.

• https://www.mds-switzerland.ch/
• https://www.sakk.ch/de/studie/myelodysplastische-syndrome-ueberpruefung-der-einhaltung-der-richtlinien-und-deren-nutzen