Helena Jernberg Wiklund – Targeting epigenetic regulators to develop novel therapeutic strategies and precision medicine in human haematological cancers

Our research is rooted in our desire to understand how epigenetic and metabolic reconfiguration contributes to haematological cancers and develop novel strategies to target identified vulnerabilities to improve disease outcome.

Two women in labcoats doing work in the lab.

Photo: Mikael Wallerstedt

Our platform portfolio includes expertise in genome-wide epigenomics analyses, long-term bioinformatics support (WABI) from the national bioinformatics infrastructure (NBIS), and induction into the bioinformatics advisory programme for PhD students.

In addition, we have both long-standing and novel national and international collaborations with clinicians and experts in machine learning and innovative sequencing technologies. These provide essential tools in our endeavour to identify novel concepts for tumour development and precision treatment strategies.

The path for new treatment strategies and precision medicine in multiple myeloma

We have a longstanding focus on multiple myeloma (MM), a haematological malignancy of the elderly that is extremely genetically complex and remains incurable, and where we were among the first to identify a global epigenomic dysregulation as a disease contributing factor. Our continued track is to uncover the complex layers of aberrant epigenetic silencing in MM, which consists of a tightly intertwined collaboration of chromatin and DNA modifiers, as well as a pleiad of protein non-coding RNAs, such as miRNA and lncRNAs.

Metabolic rewiring

We strive to functionally validate the role of identified regulators and their targets for the transformation and proliferation of MM in vitro and in vivo. We have found that our ability to target the epigenome relies on metabolic rewiring, which expanded our focus to understanding the cellular metabolism in MM.

Currently, to further unravel the mechanisms that fuel survival of myeloma cells, we are exploring the lipid metabolism and specifically the abundance and role of lipid droplets in MM.

Additionally, a novel objective of our research is to investigate the blood plasma proteome of MM patients from the U-CAN biobank. The aim is to identify biomarkers for disease detection, aggressiveness, treatments response, and relapse, as well as novel therapeutic targets to improve the survival and life quality of MM patients.

Strategies for precision medicine

Our long-term goal is to identify targets essential for tumour cell survival and explore their implementation into clinically relevant strategies for precision medicine.

To study molecular mechanisms and therapeutic use of target proteins in survival pathways of MM, we are using highly clinically relevant models of human MM. These consists of primary patient cells, and normal age-matched primary cells, a large panel of well-characterized authenticated cell lines representing all common genetic subtypes of MM, cell line-derived xenograft (CDX) model, as well as immunocompetent syngeneic murine models of MM.

Collaborations

To potentiate our work, we have established productive and long-lasting national and international collaborations for retrieval of primary cells (Dr. Torbjörn Karlsson, Akademiska Hospital), lipid droplet staining (Associate Prof. Christine Dyrager, UU) and pre-clinical drug screening in vivo (Prof. Elke De Bruyne, and Prof. Karin Vanderkerken, Vrije Universiteit Brussel, Belgium).

Epigenetic signatures pave the way for precision medicine in childhood cancer

Using our experience in MM, we have now endeavoured on investigating how epigenomic alterations define a subset of acute lymphoblastic leukaemia (ALL) occurring in children during their first year of life. For these cases, limited improvements have been achieved. despite decades of research. In both infant ALL (iALL) and MM, further understanding of the biology is essential to tackle the disease complexity.

Previous transcriptomic efforts have provided insufficient understanding of the aggressive nature of ALL in particularly infants. Epigenomic studies have so far not investigated infants separately and have mainly focused on the overactivation of the KMT2A/MLL-r targets. Comprehensive mapping of the chromatin landscape and the protein non-coding transcriptome, including the active promoter-enhancer network in iALL, is lacking. Therefore, knowledge on the mechanisms underlying disease development in patients carrying germline KMT2A/MLL and lacking other known genetic alterations is urgently needed.

Targets for new treatments

Given the very large number of uncharacterized RNAs that interact with chromatin and are likely to regulate its functions, we aim to generate a comprehensive map of non-coding RNA transcripts and chromatin modifications of interest in iALL patient cells and cell lines. Additionally, we are performing scRNA-seq on our own cohort of patient samples and applying rule-based machine learning in an innovative approach to stratify cell populations and patient groups. The overall aim is to identify targets for novel treatments in this particularly challenging disease group.

Collaborations

This project is initiated within a Nordic translational network with preclinical and clinical expertise (Prof. Arja Harila-Saari, Akademiska Hospital; Associate Prof. Rita Niinimäki, Oulu University Hospital, Finland and Associate Prof. Andreas Lennartsson, KI) and further potentiated by high-impact expertise in rule-based machine learning (Prof. Jan Komorowski, UU) and innovative sequencing technologies (Prof. Piero Carninci, RIKEN, Japan/Human Technopole, Italy).