Chronic lymphocytic leukemia (CLL) / Lymphoma
PI: Professor Richard Rosenquist Brandell
Chronic lymphocytic leukemia (CLL) is characterized by accumulation of monoclonal B cells in secondary lymphoid organs, bone marrow and peripheral blood. The median age at diagnosis is 71 years and men are more frequently affected than women. The disease is clinically and biologically heterogeneous, ranging from indolent with no treatment requirement, to a very aggressive disease characterized by chemorefractoriness and poor survival. In clinical practice, two staging systems are used (Rai and Binet) however, despite their clinical utility, they are unable to predict which patients with low tumor burden will experience an aggressive disease as opposed to an indolent course. There are currently several molecular markers that stratify CLL into prognostic subgroups, the most important of which are the mutational status of the immunoglobulin heavy variable (IGHV) genes, as well as recurrent chromosomal aberrations, where deletion of 17p (harboring the TP53 gene) is associated with an aggressive disease course and poor outcome. To this day CLL remains incurable but novel therapies using antibodies and small molecule inhibitors have advanced the field substantially.
Four main research areas
Our research projects can be subdivided in four main areas. These are:
- Defining the molecular make-up of CLL subsets expressing stereotyped B-cell receptors, which currently represent the most meaningful homogeneous subgroups to investigate. We use multiple high throughput, next-generation sequencing (NGS) technologies, including whole-genome-, transcriptome- and single-cell sequencing, as well as high-resolution methylation arrays in a clinically well-characterized CLL cohort that express stereotyped B-cell receptors. Functional analyses are performed on selected mutations/transcripts to study their effects at a cellular level by utilizing knock-down (shRNA, CRISPR/Cas9) or transfection assays in CLL cell lines.
- Identifying dysregulated intracellular signaling pathways and processes in distinct CLL subsets. We use different OMICs approaches including RNA-sequencing and proteomics that enables in-depth analyses of dysregulated signaling pathways in CLL. We also apply phospho-flow cytometry that measures protein phosphorylation events at single cell level and allows for simultaneous analysis of multiple signaling proteins and pathways. Focus is on B-cell receptor, MAPK/ERK, STAT and NF-kB signaling pathways.
Understanding resistance mechanisms in CLL using NGS and high throughput drug screening, with a focus on patients that relapse within a short period of receiving therapy. We combine whole-exome/genome sequencing in primary cells in pre- and post-treated samples from patients receiving small molecule inhibitors. Additionally, we carry out comprehensive high throughput drug testing on tumor cells from CLL patients relapsing after receiving targeted therapy in order to systematically identify drug sensitivities and resistance patterns.
- Validating, harmonizing and implementing NGS-based assays for clinical routine diagnostics. For this purpose, we work together with the European Research Initiative in CLL (ERIC) and perform multicenter validation of novel genetic findings and assays. We assess the clinical impact of recurrent mutations in large well-annotated international series of CLL cases for which both molecular and clinical characteristics are available. Once validated, new biomarkers or assays can be transferred at a national level to routine diagnostics, using the SciLifeLab Diagnostics Development platform or Genomic Medicine Sweden.