From April 2014 until January 2018, Michael Daskalakis was working as a postdoctoral fellow in the Division of Cancer Epigenomics of Prof. Christoph Plass at the German Cancer Research Center (DKFZ) in Heidelberg, Germany. By using genome wide analysis of transcription start sites (TSS) (Cap analysis of gene expression (CAGE) sequencing), methylation status (whole-genome bisulfite sequencing) and chromatin dynamics (Chromatin-immunoprecipitation (ChIP) sequencing) as well as functional assays in a cell line model, he and his co-workers were able to demonstrate a genome-wide reactivation of long terminal repeat elements (LTR). In collaboration with another research group of the DKFZ, they could confirm the results in a neuroblastoma mouse xenograft model. Michael Daskalakis presented and discussed these research results at several national and international meetings (e.g. German Society for Hematology and Oncology (DGHO), European Association of Hematology (EHA), American Society of Hematology (ASH)) and they have been published in Nature Genetics (2017) and in Cell Cycle (2018).

In collaboration with Christian Flotho, Childrens Hospital for Hematology and Oncology, University of Freiburg, Germany, Michael Daskalakis participated in the investigation of treatment effects of 5-azacytidine versus cytarabine (conventional chemotherapeutic) using a xenotransplant mouse model for Juvenile Myelomonocytic Leukemia (JMML). Both compounds strongly reduced JMML organ infiltration but only 5-Aza depleted the early CD34+ stem and progenitor cells. Human cells isolated from azacitidine-treated mice failed to initiate leukemia in secondary recipients whereas JMML cells obtained from animals treated with cytarabine were serially transplantable. The antileukemic effect of azacitidine was accompanied by dramatic global DNA demethylation with near-complete loss of fully methylated CpG sites and reactivation of endogenous retroviral sequences. The data highlighted an important advantage of azacitidine over conventional cytostatic agents in the treatment of JMML and thus encourage the further clinical development of DNA-hypomethylating agents for this disease (Leukemia 2019).

Major achievements of the last 5 years

During his time as an attending at the Inselspital Bern, Michael Daskalakis collaborated in a multicenter phase II trial investigating the effects of the telomerase inhibitor Imetelstat in patients with Essential Thrombocythemia. The study showed rapid and durable complete hematologic responses in 16/18 patients and molecular responses in 8/10 patients with JAK2V617F mutation (NEJM 2015).

During his postdoctoral fellowship at the German Cancer Research Center (DKFZ) in Heidelberg, Michael Daskalakis and his collaborating partners completed a genome-wide study showing reactivation of endogenous retroviral elements (ERVs) upon epigenetic drug treatment. The ERV reactivation results in numerous fusion transcripts that encode novel protein isoforms with predicted abnormal functions or immunogenic potential. They could confirm this effect, that is called “viral mimicry”, in different cell line models as well as in a Neuroblastoma mouse model and in normal peripheral blood mononuclear cells of a small cohort of three children who have been treated for their solid tumor with the HDAC-inhibitor Vorinostat (Nature Genetics 2017, Cell Cycle 2018).

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for children with Juvenile Myelomonocytic Leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are urgently needed. Participating in a collaboration with the Childrens Hospital or Hematology and Oncology, University of Freiburg, Germany, we were comparing the treatment effects of 5-azacytidine (AZA) versus cytarabine (conventional chemotherapeutic) by using a JMML xenotransplant mouse model and showing a therapeutic advantage of epigenetic therapy over conventional treatment prior to transplantation (Leukemia 2019). These results encouraged the colleagues from Freiburg to conduct a phase 2, multicenter, open-label study evaluating safety and anti-leukemia activity of AZA monotherapy prior to HSCT in children with newly diagnosed JMML (ASCO 2019).

Recently, Michael Daskalakis received as a co-applicant a substantial grant funding from the Personalized Health and Related Technologies (PHRT #2019-717, 3rd PHRT call) for the multi-omics project “Characterization of Oncospecific Protein Isoforms as Targets for Myelodysplastic Syndromes” using biobanked samples from the Swiss MDS Registry/Biobank (SMRB) platform (WP6). This will allow him to characterize onco-specific protein isoforms derived from alternative splicing events (like retroviral elements and others) and to search for association of identified ATs with treatment response and/or prognosis of the disease (diagnostic and/or prognostic biomarker).

Ongoing projects

Since 2019, the applicant is establishing his own epigenetic research group and started investigating LTR expression in sequential peripheral blood mononuclear cell (PBMC) samples of AML- and MDS-patients treated with 5-Azacytidine. Using qRT-PCR and digital PCR analysis, treatment response correlated with LTR expression over several treatment cycles with 5-Azacytidine in three AML and four MDS patients. The Bernische Krebsliga (Bernese Cancer League) approved an applicants` grant proposal in 2019 that allows him to investigate additional AML- and MDS-patients for LTR expression. In a collaboration with Prof. R. Greil and PD Lisa Pleyer, 3rd Medical Department for Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Paracelsus Medical University, Salzburg, Austria, he gets provided with sequential samples from AML and MDS patients for translational studies on ERV expression. The study aims to provide a biological marker for epigenetic treatment response and/or to propose an improved prognostic algorithm in e.g. AML, utilizing a comprehensive model that includes mutational status, cytogenetic status, coding gene expression and classes of ERV expression.  

List of collaborators

National

• Prof. Dr. med. Nicolas Bonadies, MDS Center of Excellence, University Hospital of Hematology, Inselspital Bern, Switzerland.
• Prof. Dr. med. Gabriela Maria Baerlocher, Stem Cell Laboratory, University Hospital of Hematology, Inselspital Bern, Switzerland.
• PD Dr. Elisabeth Oppliger Leibundgut, Molecular Diagnostics, University Hospital of Hematology, Inselspital Bern, Switzerland.

International

• Prof. Christoph Plass, German Research Cancer Center (DKFZ), Heidelberg, Germany.
• Prof. Dr. med. Richard Greil and Prof. Dr. med. Lisa Pleyer, 3rd Medical Department, Hematology and Oncology, University Hospital, Salzburg, Austria.
• Prof. Dr. med. Michael Lübbert, University Hospital, Freiburg, Germany: Former mentor during my residency at the University Hospital Freiburg, Germany.
• Prof. Dr. med. Olaf Witt, DKFZ and "Translationale Kinderonkologie" Hopp-Kindertumorzentrum (KiTZ), Heidelberg, Germany.
• Dr. David Brocks: Postdoctoral Fellow in the Group of Amos Tanay at the Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot, Israel.
• Prof. Ting Wang, Department of Genetics, The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.

Funding support

• Bernische Krebsliga
• PHRT project #2019-717

Publication list

• Orcid
• Web of Science ResearcherID: AAH-9217-2019
• My NCBI