"Clonal evolution represents a central feature of tumor progression and relapse. Chronic lymphocytic leukemia (CLL) is a valuable model to study this process due to a high prevalence, initially slow progression and the easy availability of samples. Recent large-scale sequencing studies have identified putative driver genetic events of CLL, uncovered the vast inter-personal and intratumoral genetic heterogeneity in CLL and have linked the presence of aggressive subclonal mutations with clonal evolution and poorer outcome. The patterns of different aberrations within the same sample suggest a temporal hierarchy in acquisition of genetic events, and a stepwise transformation of disease from diagnosis to later more aggressive stages. To directly test these ideas, I will systematically examine the clonal dynamics of a cohort of 17 CLL patients that were recurrently sampled over years from diagnosis until the time of first treatment. Through this longitudinal study, I will seek to identify the early events in this initially indolent malignancy leading to disease progression and how the order of genomic aberrations dictates tumor fate and biology (Aim 1). To directly test the functional impact of these early genetic events on B cell biology, we will utilize novel TALEN genome-engineering technology to generate cell lines harboring key mutation events (Aim 2). The generation of these isogenic cell lines will enable me to determine the relative fitness of putative CLL drivers in vitro and to study the effect of established and novel cytotoxic and targeted drugs on the dynamics amongst CLL subpopulations (Aim 3).
Answering these questions will facilitate translation of novel genetic insights towards the development of individualized diagnostic and therapeutic management of CLL."
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