Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in the west. The clinical course and eventual outcome of CLL is highly variable. It is accepted that intratumor heterogeneity, at the genetic and cellular levels, is the main force driving both tumor development and treatment resistance. At the genetic level, there is no single gene mutation characteristic of the disease and CLL cells, but also to some extend hematopoietic progenitors, in a given patient may carry different burden of different mutations affecting different pathways. At the cellular level, leukemic cells remain responsive to multiple stimuli originating from microenvironment but with different intensity and effect. The aim of this project is to apply next generation sequencing technologies investigate intratumor heterogeneity in chronic lymphocytic leukemia (CLL) to investigate the impact of in vitro treatment and extracellular stimuli on tumor heterogeneity and cellular behavior will also be analyzed. Experimental and clinical data will be integrated using mathematical tools to build up a model allowing prognosticating disease evolution, treatment outcome and resistance. It is expected that this work will have important consequences for the future disease management in CLL by the prevention of progression, treatment resistance, and bringing the right combination therapy to the right patients.
