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Identification and functional dissection of key genetic events in early chronic lymphocytic leukemia

Final Report Summary - CLL_INCLONEL (Identification and functional dissection of key genetic events in early chronic lymphocytic leukemia)

Clonal evolution represents a central feature of tumor progression and relapse. Chronic lymphocytic leukemia (CLL) is a valuable model to study this process using novel sequencing technologies due to a high disease prevalence, initially slow progression and the easy availability of highly pure samples. To understand the biological impact of findings arising from characterization of patient samples, experimental systems are warranted.

First objective of this project was to study genomic dynamics during CLL progression from diagnosis until the time of first treatment by chemotherapy and later upon relapse. A unique cohort of 21 CLL patients that were recurrently sampled over many years was available. Based on genetic and epigenetic together with clinical kinetic characterization of these samples, the project gained insights on the association and possible interactions between these different features across the entire disease trajectory from diagnosis up to relapse. To our knowledge, the project also represents the first direct integrative analysis of tumor growth kinetics together with genetic and epigenetic dynamics. The results of this study inspire further studies which promise possibilities to anticipate and therapeutically address evolutionary plasticity in cancer as early as at diagnosis.

To directly test the functional impact of genetic events on B cell biology, cell line models using CRISPR/Cas9 were developed, based on which the fitness impact of putative CLL drivers can now be studied in vitro. These models also serve to study the effect of established and novel drugs in the context of selected cancer mutations in B cells.

The final step toward implementation of gained insights and skills in Austria was the development of a targeted sequencing panel for cancer mutations which will be combined with an ex vivo screening for drug sensitivity of tumor cells from hematological patients. This will directly and immediately improve treatment and prognostication for patients in Austria. Implementation for clinical diagnostics and decision-making is planned for 2018. An integral experimental part of this panel will in parallel assess the potential for replacement of expensive established routine diagnostics, aiming to explore possibilities for cost reductions while at the same time obtaining higher quality information. Moreover, Dr. Gruber identified and characterized a unique CLL patient sample cohort in Vienna, which will be analyzed by chromatin profiling and targeted sequencing. This will serve to translate the new insights Dr. Gruber gained in Boston toward diagnostic means that will aid to improve treatment decisions for CLL patients.