Linda Holmfeldt’s research on molecular characterization of acute leukemia

The goal with our research is to identify the underlying causes of acute leukemia formation, progression and treatment resistance. A better understanding of how the leukemia cells function is likely to pave the way for more efficient and less toxic treatment options. In addition, we hope that our studies will lead to simplified and less invasive leukemia discovery and improved risk stratification.

What are the underlying causes of progression and therapy resistance of acute myeloid leukemia?

Svea Stratmann, Jitong Sun, Sarah Younes

To identify which alterations that favor primary treatment failure and/or the outgrowth of resistant relapse clones, we perform unbiased multilevel analyses comparing newly diagnosed and relapse AML specimens.

Complementary high-resolution techniques are used to identify any alterations that may explain treatment failure or the onset of relapse. Techniques included are, amongst others, whole genome and/or exome sequencing, RNA sequencing, mass spectrometry analysis of the proteome as well as studies of the epigenome by DNA methylation microarrays. By employing machine learning based approaches, data generated from the above mentioned analyses are integrated to generate hypotheses that could explain tumor progression and/or therapy resistance.

To complement the exploratory studies, we functionally evaluate the hypotheses generated using a combination of biochemical- and cellular studies, as well as in vivo modelling. Finally, evaluation of novel therapeutic alternatives for AML is performed.

Scematic illustration of the pipeline for machine learning-based integration of multiomics datase
                                Pipeline for machine learning-based integration of multiomics datasets

What are the downstream consequences of aberrant epigenetic regulators in leukemia?

Mahsa Shahidi Dadras

Our previous studies of pediatric high-risk and relapsed acute lymphoblastic leukemia identified a high frequency of alterations of epigenetic modifiers. Among these, alterations in the histone H3 Lysine 27 (H3K27) methyltransferase Polycomb repressive complex 2 (PRC2) stand out, especially the catalytic subunit EZH2, which has been shown to act as both an oncoprotein and tumor suppressor in different types of malignancies. This suggests that perturbation of epigenetic regulation facilitates a reduced response to therapy and/or the onset of relapse.

We want to answer the question whether specific alterations in epigenetic regulators cause i) stochastic changes at the epigenetic level, or ii) specific and recurrently found epigenetic changes of genes that favor tumorigenesis.

One of the aims in our lab is thus to interrogate the downstream consequences of aberrant PRC2 on leukemogenesis. The approach we take includes everything from biochemical enzymatic assays utilizing purified protein complexes, through analyses at the cellular level to in vivo modelling, followed by epigenomic and transcriptomic analyses of manipulated cells.