Chronic lymphocytic leukemia (CLL), characterized by the accumulation of CD5+/CD19+ B cells in all lymphoid compartments, is the most common adult leukemia in the western world. Current standard therapies are effective albeit not curative, and the disease often relapses or become resistant to standard therapies. Developing novel therapeutic approaches for CLL has been limited by the our inability to propagate patient samples in culture for prolonged periods and the lack of appropriate cell line or mouse model.
Croce et al. recently developed such a mouse model (Eµ-TCL-1 transgenic mice) whereby the oncogene TCL-1 is overexpressed in the B cells. The original mouse strain was generated on a mixed genetic background but we have focused on mice on a pure C57BL/6 background. On this background, the transgenic mice develops a CLL-like disease at a mean age of 10.3 months with elevated lymphocyte counts corresponding to the accumulation of CD5+/CD19+ CLL-like cells in the peripheral blood as well as other lymphoid compartments (lymph nodes, spleen, bone marrow).
Using this model, we sought to investigate the use of standard or novel therapies to treat the leukemia that develop in these mice. In vitro, the leukemias isolated from sick mice showed a surprisingly wide range of sensitivity to 2-fluroadenine-9-β-D-arabinofuranoside (F-ara), the active metabolite of Fludarabine, which is the standard-of-care agent for CLL treatment. To overcome the resistance in some of the Eµ-TCL-1 leukemias to F-ara, we hypothesized that the addition of a Bcl‑2 inhibitor might sensitize them to F-ara. Strikingly, the combination of venetoclax (ABT-199) to selectively inhibit Bcl‑2 with F-ara potently killed those leukemias that were insensitive to F-ara when given as a single agent.
The goal of our ongoing studies are to further characterize this model of CLL and utilize it to test novel therapeutic approaches for treating CLL, particularly for relapse/refractory disease.