In the most common adult leukemia (chronic lymphocytic leukemia), recurrent mutations of key tumor suppressors (e.g. ATM, TP53) are described, but the deletion of two non-coding RNAs (miR-15a/16-1) is the most common genetic aberrations. As proof of this concept, a mouse model with targeted deletion of miR 15a/16-1 causes MBL, CLL and lymphoma in mice. In many ways, CLL is the prototype cancer caused by non-coding RNA deregulation. The applicants’ groups have contributed vitally to the discovery how deregulated miRs cause CLL or refractory CLL. However, a complete understanding of the role of non-coding RNAs is missing. Similarly, current genetic models can only predict roughly 50% of refractory CLL. Our approach will fill specific gaps in knowledge about the molecular mechanisms of CLL: 1) The mechanisms by which the malignant B cells avoid the death induced by therapy are unknown. 2) the causes of refractory CLL and the disease transformation to Richter syndrome (transformation to high grade lymphoma with very poor prognosis) are also unknown; 3) the role of other non-coding RNAs such as long ultraconserved genes and transcribed pyknons are not deciphered.