February 14, 2023

Characterization of Oncospecific Protein Isoforms as Targets for Myelodysplastic Syndromes

3rd Call, Pioneer Project

Short Summary

Myelodysplastic Syndromes (MDS) are heterogeneous, malignant disorders originating from blood stem cells that are characterized by insufficient blood cell production (cytopenia), aberrant maturation (dysplasia), inflammation and a propensity to evolve towards acute myeloid leukemia (AML). In this project, we will analyze biobanked samples from untreated MDS patients with a multi-omics approach (DNA, RNA and proteins) to investigate protein diversity from alternative splicing, characterize their influence on relevant clinical outcomes and identify potential novel disease-specific targets for treatment.

Goals

The aim of this project is to characterize MDS-specific or oncospecifc protein isoforms (OPIs), originating from alternative splicing, as potential targets for treatment in MDS patients using a multi-omics (DNA, RNA and proteins) approach. We will focus our investigation on MDS-specific structural and functional OPIs as potential targets for i) immune mediated treatment or ii) pharmacological inhibition of enzymatic functions.

Significance

Our analysis will provide the first complete multi-omics dataset covering somatic mutations, alternative RNA-splicing and protein isoforms from an extensively characterized MDS cohort. This will not only pioneer novel insights in disease biology (exploratory relevance), but, more importantly, it will provide an array of candidate MDS-specific biomarkers for future clinical validation and therapeutic interventions (clinical relevance). The long-term goal of this project is the identification of actionable MDS-specific drug targets (biomarkers) that represent attractive candidates for future biological and clinical validation. With the data generated, we will focus our future investigation on potential targets with anticipated clinical relevance such as i) oncospecific membrane proteins and ii) enzyme isoforms that can be actionable through immune directed treatments and pharmacological inhibition, respectively.

Background

MDS are diseases of the elderly population and remain incurable without blood stem cell transplantation. Despite the recent advances in elucidating the genetic origin of MDS, the biology and potential targets for early treatment interventions remain elusive. Splicing is an evolutionary conserved process of RNA-processing in eukaryotic cells and plays an important role in protein diversity. Alternative (or differential) splicing allows production of multiple proteins (protein isoforms) by using different combinations of genetic parts (coding exons) from a single genetic locus. Alterations in regulation of alternative splicing is involved in initiation and progression of cancer, but our current understanding in MDS remains incomplete. Protein diversity in the context of alternative splicing has not been systematically investigated in MDS patients, but is fundamental for the understanding for disease initiation and response to therapy.

Pioneer Project

Prof. Dr. med. Nicolas Bonadies

Department of Hematology and Central Hematology Laboratory and Department for BioMedical Research, Inselspital Bern and University of Bern

Consortium

Department of Hematology and Central Hematology Laboratory and Department for BioMedical Research, Inselspital Bern and University of Bern
Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich
Health 2030 Genome Center
Swiss Federal Institute of Technology Zurich (ETHZ), Department of Health Sciences and Technology (D-HEST), Institute of Translational Medicine (ITM)
ETH Zurich, NEXUS Personalized Health Technologies
Swiss Institute of Bioinformatics