Advantages and disadvantages of mouse models of chronic lymphocytic leukemia in drug discovery

Abstract

Chronic lymphocytic leukemia (CLL) is a lymphoid malignancy characterized by the proliferation and accumulation of mature CD5+ B cells in the peripheral blood (PB), bone marrow (BM) and lymphoid tissues. When the number of CD5+ B cells is lower than 5 × 108 cells/L, this entity is called monoclonal B lymphocytosis (MBL) and it is asymptomatic monoclonal or oligoclonal proliferation of B cells [Citation1]. The disease may have a stable course but also become aggressive, with frequent relapses, or even transform into an aggressive lymphoma, typically diffuse large B-cell lymphoma (DLBCL) (Richter transformation). Two major molecular subgroups have been identified: those harboring unmutated immunoglobulin heavy-chain variable region (IGHV) genes (U-CLL, ≥98% identity with the germline) and those with mutated IGHV genes (M-CLL). Genomic and epigenomic studies have elucidated multiple aspects of the pathogenesis of the disease. Nowadays CLL should be considered as a complex disease in which genetic and epigenetic mechanisms cooperate with microenvironmental factors in the malignant transformation and in leukemia progression [Citation2]. In parallel, new targeted therapies and management strategies have been developed. Due to this complexity and heterogenousity, the generation of adequate pre-clinical mouse model fully reflecting tumor biology has not yet been successfully achieved. Here we describe and discuss the mouse models developed for CLL, the most prevalent type of leukemia in adults in Western countries.