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

Our research is rooted in our previous successful work of mapping the genome-wide distribution of histone modifications and transcriptomes in tumours of haematological origin.

We have previously published material on epigenetic-mediated silencing of tumour suppressor genes by global epigenomic reconfiguration in multiple myeloma (MM).

Our aim is to uncover the underlying mechanisms leading to aberrant epigenetic silencing by histone and DNA methylation, and to functionally validate the role of identified repressed non-coding and coding genes for transformation and proliferation of MM in vitro and in vivo. Using our experience in epigenomic mapping in haematopoietic tumours, we have now expanded our research plan to include novel and tumour specific therapies that can improve the outcome of infants diagnosed with acute lymphoblastic leukaemia.

Infant acute lymphoblastic leukaemia (iALL) is a rare haematological disease, arising during the first year of life and despite decades of research, limited improvements have been observed. Due to large intra-tumour heterogeneity the identification of common causative alterations for iALL and MM has been hampered. Further understanding of the biology of iALL and MM is of primary importance to tackle the disease complexity.

Our platform portfolio includes long-term bioinformatics support (WABI) from the national bioinformatics infrastructure (NBIS), induction into the bioinformatics advisory programme and expertise in genome wide epigenomics analysis. This now provides the basis for our aim to find novel concepts for tumour development and targeted treatment strategies in MM and iALL.

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

The long-term goal of our research is to identify targets essential for tumour cell survival and explore whether their function can be blocked in parallel survival pathways. To study the molecular mechanisms and therapeutic use of target proteins in survival pathways of MM, a prerequisite has been to select and implement relevant models in vitro and in vivo.

We are presently using a highly clinically relevant model of human MM. This consists of immunocompetent syngeneic murine models of MM in vivo and in vitro, a large well characterized authenticated panel of cell lines representing all common genetic subtypes of MM, primary patient cells, and normal age-matched primary cells.

Previously accomplished results in our MM model have generated proof-of-principle that EZH2 and other histone modulators are attractive targets for intervention, and that survival circuits act via gene silencing by epigenetic mechanisms. In fact, our recent work shows a comprehensive interplay between the epigenome and the metabolome in MM. The hypothesis that tumour stemness may lie within a novel tumour associated epigenetically silenced gene signature is an attractive indication since it may be reverted. Genes could also be reactivated by pharmacological intervention.

Epigenetic signatures pave the way for precision medicine in childhood cancer

The overall aim of this project is to find a biological and clinical rational for novel and specific therapies that may increase survival for infant acute lymphoblastic leukaemia (iALL) The project is based on the group’s previous work of mapping the genome-wide distribution of histone modifications in tumours of hematopoietic origin. Our results so far have highlighted the use of more precise treatment by targeting epigenetic traits (recently reviewed by us).

The current focus is to map the overall landscape of a large panel of histone modifications, to provide a complete catalogue of regulatory units in the patient iALL genome. The ultimate goal is to identify novel biomarkers and therapeutic strategies of clinical value.

We have initiated a joint programme in a Nordic translational network with preclinical and clinical expertise. We will use infant acute lymphoblastic leukaemia (iALL) patient samples to construct an epigenomic map unique to this disease. We will also decipher the underlying mechanisms leading to aberrant epigenetic silencing and validate functionally the role of repressed genes for transformation and proliferation of this tumour. Our current projects are described on a separate page.