Epigenetics of chronic lymphocytic leukemia

Aberrant DNA methylation has been implicated to play a stronger role in tumorigenesis and is associated with tumor aggressiveness and inferior outcome in various cancer types. Consequently, using de-methylating agents such as 5-aza-deoxycytidine as treatment options is currently under investigation for hematological malignancies. Alongside DNA methylation, histone modifications are the other well-studied epigenetic marks implicated in many leukemia and cancers. Histone modifications have been shown to regulate DNA methylation of many cancer related genes. Silencing histone modifications (H3K9me3 and H3K27me3) are generally coupled with DNA methylation for long term gene silencing and hence we could expect that along with the distinct methylation profiles, these entities may also contain specific histone modification patterns that are unique for each disease or within the prognostic subgroups. Growth factors, which maintain cellular homeostasis through determining the cellular fates, are often subverted in cancer. While their connections to protein coding RNAs are well known in regulating growth factor dependent cellular signaling cascades, the connection between growth factors and non-coding RNA, in particular long noncoding RNAs (lncRNAs), has been poorly investigated. Considering that lncRNAs have a wide-range of actions in cancer-associated pathways, characterizing growth factor controlled lncRNAs could devise novel therapeutic options for difficult to treat leukemias.

My current research is focused on unraveling various kinds of epigenetic modifications mainly in chronic lymphocytic leukemia (CLL). CLL is the most common adult leukemia in Western world and characterized by clonal proliferation and accumulation of long-lived neoplastic B-cells. CLL is a biologically and clinically heterogeneous malignancy with varying clinical course, and yet remains an incurable disease. Recent advancements in global analyses methods enable us to identify epigenetically regulated genes with prognostic and therapeutic values. Since epigenetic changes are reversible and are being aggressively pursued for therapeutic interventions, characterizing in detail the role and mechanism of non-coding RNA gene regulation and global epigenetic changes in well-characterized prognostic sub-groups of CLL is very important. My research mainly applies next generation sequencing techniques like RNA seq, Me-DIP sequencing, hMe-DIP seq, ChIP-sequencing and 450K high-resolution DNA methylation arrays. We employ pyrosequencing, bisulfite sequencing, quantitative RT-PCR, lenti viral transductions, and protein expression analysis to characterize the genes that show differential epigenetic marks in different prognostic subgroups. By employing state of the art technologies, we hope to find novel biomarkers and targets for diagnosis, prognosis and prediction of response to drug therapy.

Together with our neighboring groups Lars Palmqvist, Linda Fogelstrand and Julia, we form the Leukemia Research Laboratory, aiming for a fruitful hematological research environment and continuous translation of research results into clinical diagnostics.