AbstractsBiology & Animal Science

Chronic lymphocytic leukemia (CLL) is characterized by an extremely heterogeneous clinical course, ranging from stable indolent disease to overt disease requiring immediate treatment. In addition, responses to therapy vary between patients. Although important progress has been made in the treatment of CLL, especially with the introduction of chemo immunotherapeutic approaches as well as drugs targeting the B-cell receptor pathway or the apoptosis machinery, none of the available regimens are curative and relapses do occur. Only less than half of the relapses following conventional treatment regimens can be explained by known established molecular markers. Additionally these treatment regimens cause considerable toxicity to patients which is generally too toxic for frail elderly patients, who constitute the majority of CLL patients. Therefore, in this thesis, molecular and biological characteristics involved in CLL leukemogenesis are addressed with the aim (i) to identify novel relevant markers that can predict prognosis and that can distinguish patients that respond to patients that do not respond to specific treatment regimens and (ii) to identify targets for therapy which enable the design of novel targeted treatment options which are effective without unnecessary toxic side-effects. In short, in this thesis we further explored T-cell disturbances in CLL and found that, in contrast to total T cells, CMV-specific T cells are intact in CLL. Additionally, we further explored ATM-TP53 responses in CLL cells with respect to chemoresistance and found that mutations in SF3B1 which confer an adverse prognosis are associated with a defective DNA-damage response. Finally, we observed that intra-tumoral genetic heterogeneity also have clinical impact on prognostication. Improving knowledge on CLL biology will enable a more personalized approach with improved efficacy and devoid of unnecessary toxicity.